Abstract

Autism is strongly associated with epilepsy, but the mechanisms that drive this association are poorly understood. Are autism-related behaviors and epilepsy different manifestations of pathological excitability or altered synaptic transmission induced by the same genetic changes in different brain structures? Or do early-life seizures themselves drive activity-dependent changes in circuits and induce or exacerbate deficits in social interaction? This chapter will review work done in the last 10 years in mouse models of Dravet syndrome, CACNA1a deficiency, several potassium channelopathies, and the CNTNAP2 knockout model of cortical dysplasia focal epilepsy syndrome to dissect mechanisms that drive the epilepsy and autism-relevant behaviors. It will also review the evidence for the causal role of epilepsy in autism. To conclude, it will discuss new directions for research in the coming decade, driven by the development of new technologies.

The Association of Autism and Epilepsy

Around 20%–30% of individuals with autism spectrum disorder (ASD) also have epilepsy (Bill and Geschwind, 2009; Tuchman et al., 2010a, 2010b; Tuchman and Rapin, 2002), though estimates vary from 5% to 40% in different surveys (Canitano, 2007), likely because of the heterogeneity in the populations sampled. This prevalence is more than an order of magnitude greater than the prevalence of epilepsy in the general population (Murphy et al., 1995), but it may be even higher in certain syndromic causes of autism. For example, 65% of individuals with maternal isodicentric duplication of 15q11.2-q13.1 have epilepsy (Conant et al., 2014), and nearly all have autism (DiStefano et al., 2020). Similarly, 80% of individuals with tuberous sclerosis (TS), a syndrome strongly associated with autism, have epilepsy (Chu-Shore et al., 2010). In fact, the presence of severe intellectual disability (ID) or motor deficits dramatically increases the risk of the development of epilepsy in children with autism, regardless of etiology (Tuchman et al., 1991). Though the severity of epilepsy associated with autism is variable, epilepsy persists into adulthood in the vast majority of patients (Danielsson et al., 2005), and sudden death from epilepsy is a major cause of death in individuals with ASD (Gillberg et al., 2010). Many of those diagnosed with autism who have never had a seizure may have subclinical seizures or very frequent interictal discharges on prolonged electroencephalogram (EEG) recordings, suggesting that the prevalence of epilepsy in autism may be higher still (Chez et al., 2006).

Despite the knowledge of this strong association for decades, many questions remain: Do frequent clinical or subclinical seizures in early childhood disrupt brain development and cause social and communicative behavioral deficits? Or alternatively, are seizures and behavioral deficits different manifestations of synaptic and excitability changes in different brain structures and not causally related to each other? Certainly, in cases which include catastrophic epilepsies of childhood where a child could have numerous seizures per day or prolonged seizures, seizures themselves could potentially interrupt the acquisition of social and language skills. In Landau- Kleffner syndrome, for example, an acquired epileptic aphasia syndrome, regression of language is associated with frequent temporoparietal epileptiform discharges emanating from brain regions critical for comprehension of speech (Deonna, 1991). These discharges can become continuous in slow-wave sleep, where they could corrupt sleep-dependent circuit remodeling or plasticity mechanisms and disrupt acquisition of language. Also, the diagnosis of epilepsy and especially infantile spasms in children with TS increases the risk of autism (Bolton et al., 2002) and could suggest that the seizures themselves play a role in the pathogenesis of autism; yet proof of direct causality is lacking in humans. Going beyond correlative findings have required experiments in animal models where the incidence of seizures within specific circuits can be controlled precisely during each developmental stage.

The Role of Animal Models for Studying Autism/Epilepsy Syndromes

With the advent of exome and genome sequencing, mutations in an increasing number of genes have been linked to syndromes presenting with autism, epilepsy, or ID (De Rubeis et al., 2014; Epi4K Consortium, 2015, 2014; Iossifov et al., 2014; Kosmicki et al., 2017; Satterstrom et al., 2020; Willsey et al., 2013; Yu et al., 2013). A significant number of these associations are highly penetrant, single-gene associations, though different classes of mutations can lead to phenotypic heterogeneity. These discoveries have inspired the generation of rodent models which use inducible, reversible, and cell-type-specific gene manipulations to address key questions: (1) How do mutations in specific cell types alter excitatory and inhibitory synaptic densities, release probabilities, and strength or intrinsic excitability of cells? (2) Can autism-relevant behaviors (social behavioral deficits and repetitive behaviors), spontaneous seizures, and cognitive deficits be modeled together in the same animal, or alternatively can these three phenotypes be dissociated by limiting genetic changes to specific brain regions, cell-types, or developmental time points? (3) Can autism-relevant behaviors, epilepsy, and cognitive deficits be reversed by genetic manipulations late in development or adulthood, or alternatively, is there a critical period beyond which manipulations are not helpful? (4) Is there a causal connection between early developmental seizures and social behavioral deficits or cognitive deficits?

This chapter will not comprehensively review the literature on ASD/ID/epilepsy genetic rodent models. Instead, it will review a small subset of studies in rodent models of genetic syndromes where autism, epilepsy, and ID are present together as a search for convergent mechanisms. These syndromes are by necessity only a small subset of genetic disorders where rodent models have been useful and many studies, including those on TSC, PTEN, CDKL5, SHANK3, SYNGAP, Rett syndrome, and others, are not reviewed. Instead, the chapter uses examples to highlight potential avenues for research in several channelopathies and in the CNTNAP2 model of cortical dysplasia focal epilepsy (CDFE) syndrome. It will also review rodent model work on the causal connection between epilepsy and social behavioral deficits. It will conclude by discussing future directions for research on mechanism and therapeutics.

Dravet Syndrome: An Ion Channelopathy Causing Refractory Seizures, Cognitive Deficits, and Autism

Dravet syndrome typically presents with prolonged seizures before age 1, usually triggered by fever. Afebrile seizures follow, and these can frequently evolve into status epilepticus. Seizure types are diverse and can include generalized or unilateral clonic seizures, generalized tonic-clonic seizures, myoclonic seizures, atypical absences, tonic seizures, or focal seizures. ID, motor deficits, hyperactivity, repetitive behaviors, and social deficits are noted between ages 2 and 5 (Dravet, 2011). De-novo mutations in the voltage-gated sodium channel SCN1a are the main genetic cause of Dravet syndrome (Claes et al., 2001), though not all mutation carriers present with typical Dravet syndrome.

Mouse models have been useful for understanding how a loss-of-function mutation in a major sodium channel, which should in principle reduce excitability, instead results in hyperexcitability, seizures, and behavioral changes. Patch-clamp studies in hippocampal neurons from Scn1a heterozygous mice showed a dramatic reduction of sodium currents and repetitive firing ability in GABAergic interneurons but no changes in excitatory neurons, implicating decreased interneuron excitability as the main cause for seizures (Fig. 59–1A,B; Tai et al., 2014; Yu et al., 2006). Conditional deletion mutants confirmed the role of SCN1a in interneurons as single-copy deletion of Scn1a specifically in GABAergic interneurons of cerebral cortex and hippocampus also resulted in seizures and death (Cheah et al., 2012). SCN1a is predominantly expressed in parvalbumin-positive (PV+) GABAergic neurons (Ogiwara et al., 2007) and specific deletion of Scn1a only in PV+ GABAergic neurons also led to spontaneous seizures, highlighting the importance of intact repetitive firing in fast-spiking interneurons in juvenile animals for preventing runaway excitation (Ogiwara et al., 2013). Interestingly, excitability deficits in PV+ interneurons are transient, decreased at P21 but normalized by P35 in somatosensory cortex (Favero et al., 2018), suggesting that sustained decreased excitability of fast-spiking interneurons may not be responsible for chronic epileptic seizures.

Figure 59–1.

 Scn1a loss of function decreases interneuron excitability and causes repetitive behaviors, social behavioral deficits, and seizures. A. Reduced sodium currents after deletion of SCN1a in GABAergic interneurons (left) but not excitatory neurons (more...)

In addition to key insights on epilepsy, Scn1a mouse models have also opened inroads into autism-relevant behaviors and cognitive deficits present in the syndrome. Mice with SCN1a haploinsufficiency exhibit hyperactivity, stereotyped behaviors, deficits in sociability, and impairments in context-dependent memory (Han et al., 2012). Similar to seizure phenotype, deletion of Scn1a in forebrain GABAergic interneurons is sufficient to cause these deficits (Han et al., 2012). Further studies have narrowed the population of GABAergic neurons that may be causing the greatest dysfunction to PV+ neurons. Deletion of Scn1a in PV+ neurons causes similar impairments (hyperactive behavior, lack of social novelty preference, and impaired spatial memory), while deletion in somatostatin-positive (SOM+) neurons has no effect; therefore, PV+ neurons likely play a key role in seizure and behavioral phenotypes of the disorder (Tatsukawa et al., 2018).

Focal SCN1a knockout/knockdown studies have been able to dissociate the brain regions leading to epilepsy, cognitive disability, and social behavioral deficits. SCN1a deletion in dorsal and ventral hippocampus leads to memory deficits and thermal seizure susceptibility, but no social behavioral deficits (Stein et al., 2019), while knockdown in medial septum and diagonal band of Broca leads to abnormal hippocampal oscillations and memory deficits only (Bender et al., 2013), suggesting that Scn1a deletion in different brain structures contributes to different dimensions of the syndrome.

Rodent models have suggested several treatments, some of which may be tested relatively rapidly in humans as they are already approved for use for other disorders. Social and cognitive deficits are rescued by low-dose clonazepam, a positive allosteric modulator of GABA_A receptors, giving both mechanistic insight and also suggesting a potential therapeutic avenue for the treatment of autism-relevant behaviors and cognitive disabilities (Han et al., 2012). Intraventricular injection of oxytocin-containing nanoparticles can also rescue sociability deficits in a knock-in model, suggesting other therapeutic modalities could be useful (Wong et al., 2021). Cannabidiol (CBD) substantially reduces the frequency, duration, and severity of seizures in the SCN1a model and improves social interaction behaviors of DS mice. Interestingly, only low-dose treatment improved sociability, while high-dose treatment was necessary for reduction of seizure frequency and duration. Surprisingly, this effect occurred not through inhibition of CB1 receptors, but mostly through the activation of the lipid activated G protein–coupled receptor GPR55 (Kaplan et al., 2017).

While mouse models can be very useful for dissecting circuits and mechanisms leading to seizures and cognitive disability, other models can be more useful for high-throughput screening studies. Large-scale unbiased screens in zebrafish models of Dravet syndrome first identified clemizole and then other serotonergic modulators, one of which, lorcaserin, decreased seizure burden in humans with the disorder (Griffin et al., 2017), demonstrating the possibility of rapid translation from basic studies to the clinic.

Calcium Channelopathies

Ion channelopathies causing epilepsy, ID, and autism extend beyond sodium channels in Dravet to other channels. One major ion channel identified has been the Ca_v2.1 P/Q-type voltage-dependent calcium channel found in presynaptic terminals and critical for transmitter release. Ca_v2.1 is composed of multiple subunits, including the pore-forming alpha-1A subunit encoded by the CACNA1A gene as well as beta, alpha-2/delta, and gamma subunits (Catterall, 1991). Mutations in CACNA1A were first associated with various neurologic familial hemiplegic migraine (Ducros et al., 2001), episodic ataxia type 2, and spinocerebellar ataxia type 6 (Jodice et al., 1997), but recent work in several families implicates the CACNA1A haploinsufficiency, a syndrome variably associated with ID, ADHD, autism, refractory absence epilepsy, febrile seizures, downbeat nystagmus, and episodic ataxia (Damaj et al., 2015).

How does loss of CACNA1A cause different manifestations of the disorder? Cell-type-specific deletion of the gene in MGE-derived interneurons in cerebral cortex (and sparing the thalamus) led to generalized absence and motor seizures by decreasing action potential–evoked transmitter release from PV+ neurons (Fig. 59–1A,B; Rossignol et al., 2013). This was surprising, given that previous work had implicated rhythmic synchronized bursting in thalamic neurons as driving absence seizures. Similar findings were seen after specific deletion of Cacna1a in PV+ neurons, but loss of perisomatic inhibition was accompanied by mTOR-dependent sprouting of SOM+ neuronal axons, which prevented motor seizures (Jiang et al., 2018). These studies highlight the importance of cortical inhibition and the complex interplay between the molecular defect and the downstream compensatory pathways which limit the expression of epilepsy. They also suggest caution with respect to mTOR inhibition as a therapeutic modality for epilepsy as inhibition may impair inhibitory mechanisms that prevent ictal onset.

In addition to seizures, PV+ neuron-specific deletion of Cacna1a induces robust behavioral changes, effectively modeling behavioral and cognitive features of the disorder in humans. PV+ neuron-specific deletion leads to decreased anxiety behavior, decreased sociability, reversal learning deficits, and impairments in selective attention on a set-shifting task (Fig. 59–2C; Lupien-Meilleur et al., 2021). Only the deficits in selective attention were also found when Cacna1a was deleted selectively in the medial prefrontal cortex (mPFC), while reversal deficits and no other deficits were induced only when Cacna1a was deleted in orbitofrontal cortex (OFC). Chemogenetic activation of PV+ neurons in mPFC rescued selective attention deficits in the model (Fig. 59–2C), while chemogenetic activation of PV+ neurons in OFC rescued reversal learning deficits, clearly linking each brain region to the corresponding deficits measured but also suggesting potential treatments for cognitive deficits in the disorder (Lupien-Meilleur et al., 2021).

Figure 59–2.

Deletion of Cacna1a in interneurons reduces GABAergic transmission, causes absence seizures, and reversibly worsens performance on an attentional set-shifting task. A. Reduced unitary IPSCs elicited by single spikes in fast-spiking inhibitory neurons (more...)

Potassium Channels: Kv4.2 and Kv7.2

While altered potassium channel expression has been implicated strongly in models of temporal lobe epilepsy for decades, recent sequencing also implicates potassium channel mutations in epilepsy, ID, and autism syndromes. Kv4.2 encodes an A-type rapidly inactivating potassium channel. The V404M Kv4.2 mutation in twins with severe infantile epilepsy, autism, and ID slows current decay, dramatically impairing the inactivation of channels that have opened (Lee et al., 2014; Lin et al., 2018). Given Kv4.2’s strong dendritic expression (Hoffman et al., 1997), these mutations could potentially alter dendritic electrogenesis that is critical for synaptic plasticity (Bittner et al., 2015, 2017).

Kv7.2 encoded by KCNQ2 is a slowly activating and deactivating potassium channel, which in association with another KCNQ3, encodes the M channel (Wang et al., 1998). It is inhibited by muscarinic acetylcholine receptor activation (Shapiro et al., 2000) and activated by the anticonvulsant retigabine (Main et al., 2000). Heterozygous loss of function of KCNQ2 (KV7.2) causes epileptic encephalopathy, ID, and autism (Kato et al., 2013; Weckhuysen et al., 2012, 2013). Mouse models show hyperactivity, repetitive grooming, decreased sociability, and elevated seizure susceptibility after kainic acid injection, thereby reproducing both autism-relevant behaviors and hyperexcitability evident in the disorder (Kim et al., 2020).

CNTNAP2

Homozygous mutations in CNTNAP2 cause cortical dysplasia focal epilepsy (CDFE) syndrome, a syndrome discovered in Old Order Amish families that is characterized by cortical dysplasia, refractory seizures, hyperactivity, inattention, ID, and autism (Strauss et al., 2006). A mouse model of the disorder reproduces many aspects of the disorder; mice have seizures, frequent interictal discharges, social behavioral deficits, repetitive behaviors responsive to risperidone, and hyperactivity (Peñagarikano et al., 2011).

How does a lack or truncation of CNTNAP2 lead to neural circuit malfunction in brain regions critical for social behavior? CNTNAP2 was first implicated in clustering potassium channels in axonal juxtaparanodes in peripheral nerves (Horresh et al., 2008; Poliak et al., 1999, 2001, 2003), suggesting altered excitability could be a culprit. However, electrophysiological studies did not show alterations of intrinsic excitability of adult mPFC excitatory or PV+ neurons; instead, laser scanning photostimulation, whole-cell recordings, and electron microscopy revealed a strong reduction of excitatory and inhibitory synaptic inputs onto L2/3 excitatory neurons without altering dendritic branching. This reduction was associated with a reduced precision of phase-locked firing to ongoing delta and theta oscillations in awake behaving animals (Lazaro et al., 2019). Beyond the local circuit level, functional magnetic resonance imaging (fMRI) studies further showed decreases in long-range functional connectivity (Liska et al., 2018). Therefore, alterations in synaptic density can lead to large-scale disruption of oscillatory synchronization and multiregional activation across large populations of neurons. In addition to decreases in inhibitory and excitatory synapse number, the absolute numbers of PV+ interneurons may also be decreased (Peñagarikano et al., 2011; Vogt et al., 2018), possibly altering the balance of somatic to dendritic inhibition.

How do these circuit alterations alter social behavior? mPFC representations of socially relevant odors are disrupted in Cntnap2 knockout (KO) mice, with increases in the “noise” levels in spontaneous activity (Levy et al., 2019). Consistent with some of these findings, optogenetic increases in the excitability of PV+ mPFC neurons or decreases in excitatory mPFC neurons rescued deficits in social behavior and hyperactivity in adult mice lacking CNTNAP2 (Selimbeyoglu et al., 2017). Social behavioral deficits could also be rescued by administration of oxytocin, stimulation of endogenous oxytocin release by a melanocortin receptor 4 agonist, or through DREADD activation of paraventricular hypothalamic neurons releasing oxytocin (Peñagarikano et al., 2015). Therefore, multiple potential intersecting pathways may exist to modulate behavioral deficits.

Within the hippocampus, a region likely critical for initiation of temporal lobe seizures suffered by patients with CDFE, there is a reduction of perisomatic but not dendritic inhibition (Jurgensen and Castillo, 2015). This impaired perisomatic inhibition could lead to aberrant synchronization and seizures.

Are these circuit and behavioral deficits all determined genetically or do other environmental factors contribute to the level of dysfunction? Recent work suggests that the gut microbiome, through regulation of the gut-brain axis, plays a key role in whether CNTNAP2-deficient animals express social behavioral deficits (Buffington et al., 2021). The authors discovered that social interaction deficits in Cntnap2 knockout (KO) mice were greatest when KO animals were exclusively housed with other KO animals. Housing wild-type and KO mice together normalized social interactions and eliminated differences in the gut microbiome species in the two different sets of animals, but it did not affect hyperactivity. Fecal microbiota transplants and selective treatments with Lactobacillus reuteri conferred the social behavioral phenotype of the donor line, strongly implicating the microbiome in mediating these differences. This work opens the door for new treatment modality based on microbiotics and suggests that environmental factors could potentially impact behavioral deficits. Whether the microbiome controls the frequency or severity of seizures in this model remains to be determined, but recent evidence suggests that the microbiome can impact seizures in animal models of epilepsy (Olson et al., 2018).

Do Seizures during Development Cause Impairments in Social Behavior?

While the presence of uncontrolled seizures, especially infantile spasms, correlates with increases in social and behavioral deficits (Bolton et al., 2002), studies in humans are necessarily correlative and do not prove a causative link. While mouse models do not show complex social and communicative behaviors of humans, they nonetheless allow the investigator to induce or prevent seizures at precise developmental time points in distinct and matched genetic backgrounds, and then assess behavioral changes. These studies can strengthen the case for a causal connection.

Results from experiments in rats with a high seizure burden during development support the notion that frequent seizures during development can induce social behavioral deficits. Fifty early-life seizures induced by chemoconvulsants resulted in social behavioral deficits in adult rats and increased the coherence of local field potentials between the hippocampus and prefrontal cortex, suggesting increased functional connectivity across brain regions (Mouchati et al., 2019). Results in mice are concordant and suggest an even lower seizure burden may be sufficient. Three seizures per day for 5 days starting at postnatal day 7 induced both spatial memory deficits and social behavioral deficits later in life (Lugo et al., 2014). Administration of bumetanide, a drug that blocks NKCC1 and hyperpolarizes the reversal potential of chloride to render GABAergic transmission inhibitory, prevents social behavioral deficits induced by early-life seizures, implicating seizure-induced altered chloride homeostasis as a potential mechanism (Holmes et al., 2015).

The mechanisms of driving seizure-induced alterations of connectivity is not yet clear, but given the role of activity for the development of early circuits (Butz et al., 2009), it is possible that seizures highjack these mechanisms and, through induction of synaptic and structural plasticity, alter social interaction and learning and memory. Experiments in auditory cortex clearly demonstrate this possibility. Neonatal seizures, induced by PTZ immediately before the critical period for auditory map plasticity, prevent plasticity through un-silencing of synapses only expressing NMDA receptors and no AMPA receptors (Sun et al., 2018). Therefore, seizures can disrupt refinement of cortical circuits by normal activity patterns. It is possible that similar changes are occurring in higher order cortical regions driving socially motivated behaviors. Another potential mechanism is induction of mTOR by seizures themselves. Studies in forebrain-specific TSC1 knockout model have shown that seizures spreading to dorsal raphe (DR) can induce mTOR in this structure and drive social behavioral deficits, even though DR neurons do not have deletion of TSC1 (McMahon et al., 2015). Consistent with these findings, deletion of TSC1 in DR by itself can induce social behavioral deficits (McMahon et al., 2015). This may give further impetus to the use of rapamycin or other mTOR modulators in mTOR related neurodevelopmental disorders.

Future Directions

As exome and genome sequencing of cases progresses, the number of genes associated with epilepsy/autism syndromes will increase. It will be critical to determine which pathways these genes converge upon. In particular, it may be useful to find which gene mutations dissociate autism, epilepsy, and ID and then probe the developmental expression patterns of the genes to highlight critical brain regions and cell types. It is highly likely that single-cell RNA sequencing techniques (Islam et al., 2014), which allow high-throughput transcriptional assays in specific cell types, will be useful for these endeavors. Future research will take advantage of intersectional approaches to further delineate the subpopulations of neurons that may be acting as pathological hubs (Fenno et al., 2014; Poulin et al., 2018). Better ways of targeting the activity, gene expression patterns, or signal transduction pathways in these cells could lead to better treatments with fewer side effects. Importantly, new imaging and electrophysiology tools now allow investigators to probe the activity patterns of hundreds to thousands of neurons simultaneously, and provide methods for identification of cell types in behaving animals (Aharoni et al., 2019; Jun et al., 2017; Shuman et al., 2020). New techniques are emerging that allow precise manipulations of activity (Packer et al., 2012; Robinson et al., 2020), which could potentially be driven by real-time analysis of population activity patterns (Mitani and Komiyama, 2018). Patterned light stimulation can be directed onto specific cells selectively, allowing investigators to test hypotheses as to which neuronal sets initiate, maintain, or terminate seizure or aberrant social behaviors. Finally, Crispr-Cas9 techniques (Doudna and Charpentier, 2014) have been used in humans to edit the genome and treat disorders such as hypercholesterolemia in nonhuman primates (Musunuru et al., 2021) and amyloidosis in humans (Gillmore et al., 2021). These techniques are poised to have a dramatic impact on the lives of individuals with epilepsy and autism. Yet, for these techniques to yield benefits, the precise developmental time point where gene manipulations could have a potential impact needs to be identified. For some disorders, manipulations even in adults could be effective. For others, early interventions, even in utero, will be necessary. Developing methods for driving robust gene editing in the central nervous system will be a prerequisite.

Given these monumental advances, the next decade will bring discoveries that will improve the lives of individuals with autism, epilepsy, and ID syndromes. The networked world where parents of individuals with similar genetic syndromes can find each other, raise awareness, and recruit researchers has the potential to accelerate discovery and drive translation of therapies.

References

1. Aharoni, D., Khakh, B.S., Silva, A.J., Golshani, P., 2019. All the light that we can see: a new era in miniaturized microscopy.  Nat. Methods 16, 11–13. https://doi​.org/10.1038​/s41592-018-0266-x [PMC free article: PMC8320687] [PubMed: 30573833]
2. Bender, A.C., Natola, H., Ndong, C., Holmes, G.L., Scott, R.C., Lenck-Santini, P.-P., 2013. Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol. Dis. 54, 297–307. https://doi​.org/10.1016/j​.nbd.2012.12.021 [PMC free article: PMC3628954] [PubMed: 23318929]
3. Bill, B.R., Geschwind, D.H., 2009. Genetic advances in autism: heterogeneity and convergence on shared pathways.  Curr. Opin. Genet. Dev. 19, 271–278. https://doi​.org/10.1016/j​.gde.2009.04.004 [PMC free article: PMC2715429] [PubMed: 19477629]
4. Bittner, K.C., Grienberger, C., Vaidya, S.P., Milstein, A.D., Macklin, J.J., Suh, J., Tonegawa, S., Magee, J.C., 2015. Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons.  Nat. Neurosci. 18, 1133–1142. https://doi​.org/10.1038/nn.4062 [PMC free article: PMC4888374] [PubMed: 26167906]
5. Bittner, K.C., Milstein, A.D., Grienberger, C., Romani, S., Magee, J.C., 2017. Behavioral time scale synaptic plasticity underlies CA1 place fields.  Science 357, 1033–1036. https://doi​.org/10.1126/science.aan3846 [PMC free article: PMC7289271] [PubMed: 28883072]
6. Bolton, P.F., Park, R.J., Higgins, J.N.P., Griffiths, P.D., Pickles, A., 2002. Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex.  Brain J.  Neurol. 125, 1247–1255. https://doi​.org/10.1093/brain/awf124 [PubMed: 12023313]
7. Buffington, S.A., Dooling, S.W., Sgritta, M., Noecker, C., Murillo, O.D., Felice, D.F., Turnbaugh, P.J., Costa-Mattioli, M., 2021. Dissecting the contribution of host genetics and the microbiome in complex behaviors.  Cell 184, 1740–1756.e16. https://doi​.org/10.1016/j​.cell.2021.02.009 [PMC free article: PMC8996745] [PubMed: 33705688]
8. Butz, M., Wörgötter, F., van Ooyen, A., 2009. Activity-dependent structural plasticity.  Brain Res. Rev. 60, 287–305. https://doi​.org/10.1016/j​.brainresrev.2008.12.023 [PubMed: 19162072]
9. Canitano, R., 2007. Epilepsy in autism spectrum disorders.  Eur. Child Adolesc. Psychiatry 16, 61–66. https://doi​.org/10.1007​/s00787-006-0563-2 [PubMed: 16932856]
10. Catterall, W.A., 1991. Structure and function of voltage-gated sodium and calcium channels.  Curr. Opin. Neurobiol. 1, 5–13. https://doi​.org/10.1016​/0959-4388(91)90004-q [PubMed: 1668312]
11. Cheah, C.S., Yu, F.H., Westenbroek, R.E., Kalume, F.K., Oakley, J.C., Potter, G.B., Rubenstein, J.L., Catterall, W.A., 2012. Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome.  Proc. Natl. Acad. Sci. U. S. A. 109, 14646–14651. https://doi​.org/10.1073/pnas.1211591109 [PMC free article: PMC3437823] [PubMed: 22908258]
12. Chez, M.G., Chang, M., Krasne, V., Coughlan, C., Kominsky, M., Schwartz, A., 2006. Frequency of epileptiform EEG abnormalities in a sequential screening of autistic patients with no known clinical epilepsy from 1996 to 2005.  Epilepsy Behav. EB 8, 267–271. https://doi​.org/10.1016/j​.yebeh.2005.11.001 [PubMed: 16403678]
13. Chu-Shore, C.J., Major, P., Camposano, S., Muzykewicz, D., Thiele, E.A., 2010. The natural history of epilepsy in tuberous sclerosis complex.  Epilepsia 51, 1236–1241. https://doi​.org/10.1111/j​.1528-1167.2009.02474.x [PMC free article: PMC3065368] [PubMed: 20041940]
14. Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., De Jonghe, P., 2001. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.  Am. J. Hum. Genet. 68, 1327–1332. https://doi​.org/10.1086/320609 [PMC free article: PMC1226119] [PubMed: 11359211]
15. Conant, K.D., Finucane, B., Cleary, N., Martin, A., Muss, C., Delany, M., Murphy, E.K., Rabe, O., Luchsinger, K., Spence, S.J., Schanen, C., Devinsky, O., Cook, E.H., LaSalle, J., Reiter, L.T., Thibert, R.L., 2014. A survey of seizures and current treatments in 15q duplication syndrome.  Epilepsia 55, 396–402. https://doi​.org/10.1111/epi.12530 [PubMed: 24502430]
16. Damaj, L., Lupien-Meilleur, A., Lortie, A., Riou, É., Ospina, L.H., Gagnon, L., Vanasse, C., Rossignol, E., 2015. CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.  Eur. J. Hum. Genet. EJHG 23, 1505–1512. https://doi​.org/10.1038/ejhg.2015.21 [PMC free article: PMC4613477] [PubMed: 25735478]
17. Danielsson, S., Gillberg, I.C., Billstedt, E., Gillberg, C., Olsson, I., 2005. Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood.  Epilepsia 46, 918–923. https://doi​.org/10.1111/j​.1528-1167.2005.57504.x [PubMed: 15946331]
18. De Rubeis, S., He, X., Goldberg, A.P., Poultney, C.S., Samocha, K., Cicek, A.E., Kou, Y., Liu, L., Fromer, M., Walker, S., Singh, T., Klei, L., Kosmicki, J., Shih-Chen, F., Aleksic, B., Biscaldi, M., Bolton, P.F., Brownfeld, J.M., Cai, J., Campbell, N.G., Carracedo, A., Chahrour, M.H., Chiocchetti, A.G., Coon, H., Crawford, E.L., Curran, S.R., Dawson, G., Duketis, E., Fernandez, B.A., Gallagher, L., Geller, E., Guter, S.J., Hill, R.S., Ionita-Laza, J., Jimenz Gonzalez, P., Kilpinen, H., Klauck, S.M., Kolevzon, A., Lee, I., Lei, I., Lei, J., Lehtimäki, T., Lin, C.-F., Ma’ayan, A., Marshall, C.R., McInnes, A.L., Neale, B., Owen, M.J., Ozaki, N., Parellada, M., Parr, J.R., Purcell, S., Puura, K., Rajagopalan, D., Rehnström, K., Reichenberg, A., Sabo, A., Sachse, M., Sanders, S.J., Schafer, C., Schulte-Rüther, M., Skuse, D., Stevens, C., Szatmari, P., Tammimies, K., Valladares, O., Voran, A., Li-San, W., Weiss, L.A., Willsey, A.J., Yu, T.W., Yuen, R.K.C., Cook, E.H., Freitag, C.M., Gill, M., Hultman, C.M., Lehner, T., Palotie, A., Schellenberg, G.D., Sklar, P., State, M.W., Sutcliffe, J.S., Walsh, C.A., Scherer, S.W., Zwick, M.E., Barett, J.C., Cutler, D.J., Roeder, K., Devlin, B., Daly, M.J., Buxbaum, J.D., 2014. Synaptic, transcriptional and chromatin genes disrupted in autism.  Nature 515, 209–215. https://doi​.org/10.1038/nature13772 [PMC free article: PMC4402723] [PubMed: 25363760]
19. Deonna, T.W., 1991. Acquired epileptiform aphasia in children (Landau-Kleffner syndrome).  J. Clin. Neurophysiol. Off. Publ. Am. Electroencephalogr. Soc. 8, 288–298. https://doi​.org/10.1097​/00004691-199107010-00005 [PubMed: 1918334]
20. DiStefano, C., Wilson, R.B., Hyde, C., Cook, E.H., Thibert, R.L., Reiter, L.T., Vogel-Farley, V., Hipp, J., Jeste, S., 2020. Behavioral characterization of dup15q syndrome: Toward meaningful endpoints for clinical trials.  Am. J. Med. Genet. A. 182, 71–84. https://doi​.org/10.1002/ajmg.a.61385 [PMC free article: PMC7334030] [PubMed: 31654560]
21. Doudna, J.A., Charpentier, E., 2014. Genome editing. The new frontier of genome engineering with CRISPR-Cas9.  Science 346, 1258096. https://doi​.org/10.1126/science.1258096 [PubMed: 25430774]
22. Dravet, C., 2011. The core Dravet syndrome phenotype. Epilepsia 52 Suppl 2, 3–9. https://doi​.org/10.1111/j​.1528-1167.2011.02994.x [PubMed: 21463272]
23. Ducros, A., Denier, C., Joutel, A., Cecillon, M., Lescoat, C., Vahedi, K., Darcel, F., Vicaut, E., Bousser, M.G., Tournier-Lasserve, E., 2001. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel.  N. Engl. J. Med. 345, 17–24. https://doi​.org/10.1056​/NEJM200107053450103 [PubMed: 11439943]
24. Epi4K Consortium, 2015. Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy.  Ann. Neurol. 78, 323–328. https://doi​.org/10.1002/ana.24457 [PMC free article: PMC4646089] [PubMed: 26068938]
25. Epi4K Consortium, 2014. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies.  Am. J. Hum. Genet. 95, 360–370. https://doi​.org/10.1016/j​.ajhg.2014.08.013 [PMC free article: PMC4185114] [PubMed: 25262651]
26. Favero, M., Sotuyo, N.P., Lopez, E., Kearney, J.A., Goldberg, E.M., 2018. A Transient Developmental Window of Fast-Spiking Interneuron Dysfunction in a Mouse Model of Dravet Syndrome.  J. Neurosci. Off. J. Soc. Neurosci. 38, 7912–7927. https://doi​.org/10.1523/JNEUROSCI​.0193-18.2018 [PMC free article: PMC6125809] [PubMed: 30104343]
27. Fenno, L.E., Mattis, J., Ramakrishnan, C., Hyun, M., Lee, S.Y., He, M., Tucciarone, J., Selimbeyoglu, A., Berndt, A., Grosenick, L., Zalocusky, K.A., Bernstein, H., Swanson, H., Perry, C., Diester, I., Boyce, F.M., Bass, C.E., Neve, R., Huang, Z.J., Deisseroth, K., 2014. Targeting cells with single vectors using multiple-feature Boolean logic.  Nat. Methods 11, 763–772. https://doi​.org/10.1038/nmeth.2996 [PMC free article: PMC4085277] [PubMed: 24908100]
28. Gillberg, C., Billstedt, E., Sundh, V., Gillberg, I.C., 2010. Mortality in autism: a prospective longitudinal community-based study.  J. Autism Dev. Disord. 40, 352–357. https://doi​.org/10.1007​/s10803-009-0883-4 [PubMed: 19838782]
29. Gillmore, J.D., Gane, E., Taubel, J., Kao, J., Fontana, M., Maitland, M.L., Seitzer, J., O’Connell, D., Walsh, K.R., Wood, K., Phillips, J., Xu, Y., Amaral, A., Boyd, A.P., Cehelsky, J.E., McKee, M.D., Schiermeier, A., Harari, O., Murphy, A., Kyratsous, C.A., Zambrowicz, B., Soltys, R., Gutstein, D.E., Leonard, J., Sepp-Lorenzino, L., Lebwohl, D., 2021. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.  N. Engl. J. Med. 385(6), pp. 493–502. https://doi​.org/10.1056/NEJMoa2107454 [PubMed: 34215024]
30. Griffin, A., Hamling, K.R., Knupp, K., Hong, S., Lee, L.P., Baraban, S.C., 2017. Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome.  Brain J.  Neurol. 140, 669–683. https://doi​.org/10.1093/brain/aww342 [PMC free article: PMC6075536] [PubMed: 28073790]
31. Han, S., Tai, C., Westenbroek, R.E., Yu, F.H., Cheah, C.S., Potter, G.B., Rubenstein, J.L., Scheuer, T., de la Iglesia, H.O., Catterall, W.A., 2012. Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.  Nature 489, 385–390. https://doi​.org/10.1038/nature11356 [PMC free article: PMC3448848] [PubMed: 22914087]
32. Hoffman, D.A., Magee, J.C., Colbert, C.M., Johnston, D., 1997. K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons.  Nature 387, 869–875. https://doi​.org/10.1038/43119 [PubMed: 9202119]
33. Holmes, G.L., Tian, C., Hernan, A.E., Flynn, S., Camp, D., Barry, J., 2015. Alterations in sociability and functional brain connectivity caused by early-life seizures are prevented by bumetanide.  Neurobiol. Dis. 77, 204–219. https://doi​.org/10.1016/j​.nbd.2015.02.015 [PMC free article: PMC4682568] [PubMed: 25766676]
34. Horresh, I., Poliak, S., Grant, S., Bredt, D., Rasband, M.N., Peles, E., 2008. Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons.  J. Neurosci. Off. J. Soc. Neurosci. 28, 14213–14222. https://doi​.org/10.1523/JNEUROSCI​.3398-08.2008 [PMC free article: PMC2859216] [PubMed: 19109503]
35. Iossifov, I., O’Roak, B.J., Sanders, S.J., Ronemus, M., Krumm, N., Levy, D., Stessman, H.A., Witherspoon, K.T., Vives, L., Patterson, K.E., Smith, J.D., Paeper, B., Nickerson, D.A., Dea, J., Dong, S., Gonzalez, L.E., Mandell, J.D., Mane, S.M., Murtha, M.T., Sullivan, C.A., Walker, M.F., Waqar, Z., Wei, L., Willsey, A.J., Yamrom, B., Lee, Y., Grabowska, E., Dalkic, E., Wang, Z., Marks, S., Andrews, P., Leotta, A., Kendall, J., Hakker, I., Rosenbaum, J., Ma, B., Rodgers, L., Troge, J., Narzisi, G., Yoon, S., Schatz, M.C., Ye, K., McCombie, W.R., Shendure, J., Eichler, E.E., State, M.W., Wigler, M., 2014. The contribution of de novo coding mutations to autism spectrum disorder.  Nature 515, 216–221. https://doi​.org/10.1038/nature13908 [PMC free article: PMC4313871] [PubMed: 25363768]
36. Islam, S., Zeisel, A., Joost, S., La Manno, G., Zajac, P., Kasper, M., Lönnerberg, P., Linnarsson, S., 2014. Quantitative single-cell RNA-seq with unique molecular identifiers.  Nat. Methods 11, 163–166. https://doi​.org/10.1038/nmeth.2772 [PubMed: 24363023]
37. Jiang, X., Lupien-Meilleur, A., Tazerart, S., Lachance, M., Samarova, E., Araya, R., Lacaille, J.-C., Rossignol, E., 2018. Remodeled cortical inhibition prevents motor seizures in generalized epilepsy.  Ann. Neurol. 84, 436–451. https://doi​.org/10.1002/ana.25301 [PubMed: 30048010]
38. Jodice, C., Mantuano, E., Veneziano, L., Trettel, F., Sabbadini, G., Calandriello, L., Francia, A., Spadaro, M., Pierelli, F., Salvi, F., Ophoff, R.A., Frants, R.R., Frontali, M., 1997. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p.  Hum. Mol. Genet. 6, 1973–1978. https://doi​.org/10.1093/hmg/6.11.1973 [PubMed: 9302278]
39. Jun, J.J., Steinmetz, N.A., Siegle, J.H., Denman, D.J., Bauza, M., Barbarits, B., Lee, A.K., Anastassiou, C.A., Andrei, A., Aydın, Ç., Barbic, M., Blanche, T.J., Bonin, V., Couto, J., Dutta, B., Gratiy, S.L., Gutnisky, D.A., Häusser, M., Karsh, B., Ledochowitsch, P., Lopez, C.M., Mitelut, C., Musa, S., Okun, M., Pachitariu, M., Putzeys, J., Rich, P.D., Rossant, C., Sun, W.-L., Svoboda, K., Carandini, M., Harris, K.D., Koch, C., O’Keefe, J., Harris, T.D., 2017. Fully integrated silicon probes for high-density recording of neural activity.  Nature 551, 232–236. https://doi​.org/10.1038/nature24636 [PMC free article: PMC5955206] [PubMed: 29120427]
40. Jurgensen, S., Castillo, P.E., 2015. Selective Dysregulation of Hippocampal Inhibition in the Mouse Lacking Autism Candidate Gene CNTNAP2.  J. Neurosci. Off. J. Soc. Neurosci. 35, 14681–14687. https://doi​.org/10.1523/JNEUROSCI​.1666-15.2015 [PMC free article: PMC4623232] [PubMed: 26511255]
41. Kaplan, J.S., Stella, N., Catterall, W.A., Westenbroek, R.E., 2017. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome.  Proc. Natl. Acad. Sci. U. S. A. 114, 11229–11234. https://doi​.org/10.1073/pnas.1711351114 [PMC free article: PMC5651774] [PubMed: 28973916]
42. Kato, M., Yamagata, T., Kubota, M., Arai, H., Yamashita, S., Nakagawa, T., Fujii, T., Sugai, K., Imai, K., Uster, T., Chitayat, D., Weiss, S., Kashii, H., Kusano, R., Matsumoto, A., Nakamura, K., Oyazato, Y., Maeno, M., Nishiyama, K., Kodera, H., Nakashima, M., Tsurusaki, Y., Miyake, N., Saito, K., Hayasaka, K., Matsumoto, N., Saitsu, H., 2013. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation.  Epilepsia 54, 1282–1287. https://doi​.org/10.1111/epi.12200 [PubMed: 23621294]
43. Kim, E.C., Patel, J., Zhang, J., Soh, H., Rhodes, J.S., Tzingounis, A.V., Chung, H.J., 2020. Heterozygous loss of epilepsy gene KCNQ2 alters social, repetitive and exploratory behaviors. Genes Brain Behav. 19, e12599. https://doi​.org/10.1111/gbb.12599 [PMC free article: PMC7050516] [PubMed: 31283873]
44. Kosmicki, J.A., Samocha, K.E., Howrigan, D.P., Sanders, S.J., Slowikowski, K., Lek, M., Karczewski, K.J., Cutler, D.J., Devlin, B., Roeder, K., Buxbaum, J.D., Neale, B.M., MacArthur, D.G., Wall, D.P., Robinson, E.B., Daly, M.J., 2017. Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.  Nat. Genet. 49, 504–510. https://doi​.org/10.1038/ng.3789 [PMC free article: PMC5496244] [PubMed: 28191890]
45. Lazaro, M.T., Taxidis, J., Shuman, T., Bachmutsky, I., Ikrar, T., Santos, R., Marcello, G.M., Mylavarapu, A., Chandra, S., Foreman, A., Goli, R., Tran, D., Sharma, N., Azhdam, M., Dong, H., Choe, K.Y., Peñagarikano, O., Masmanidis, S.C., Rácz, B., Xu, X., Geschwind, D.H., Golshani, P., 2019. Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism.  Cell Rep. 27, 2567–2578.e6. https://doi​.org/10.1016/j​.celrep.2019.05.006 [PMC free article: PMC6553483] [PubMed: 31141683]
46. Lee, H., Lin, M.A., Kornblum, H.I., Papazian, D.M., Nelson, S.F., 2014. Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation.  Hum. Mol. Genet. 23, 3481–3489. https://doi​.org/10.1093/hmg/ddu056 [PMC free article: PMC4049306] [PubMed: 24501278]
47. Levy, D.R., Tamir, T., Kaufman, M., Parabucki, A., Weissbrod, A., Schneidman, E., Yizhar, O., 2019. Dynamics of social representation in the mouse prefrontal cortex.  Nat. Neurosci. 22, 2013–2022. https://doi​.org/10.1038​/s41593-019-0531-z [PubMed: 31768051]
48. Lin, M.-C.A., Cannon, S.C., Papazian, D.M., 2018. Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening. Proc.  Natl. Acad. Sci. U. S. A. 115, E3559–E3568. https://doi​.org/10.1073/pnas.1717082115 [PMC free article: PMC5899440] [PubMed: 29581270]
49. Lugo, J.N., Swann, J.W., Anderson, A.E., 2014. Early-life seizures result in deficits in social behavior and learning.  Exp. Neurol. 256, 74–80. https://doi​.org/10.1016/j​.expneurol.2014.03.014 [PMC free article: PMC4361039] [PubMed: 24685665]
50. Lupien-Meilleur, A., Jiang, X., Lachance, M., Taschereau-Dumouchel, V., Gagnon, L., Vanasse, C., Lacaille, J.-C., Rossignol, E., 2021. Reversing frontal disinhibition rescues behavioural deficits in models of CACNA1A-associated neurodevelopment disorders.  Mol. Psychiatry.  https://doi​.org/10.1038​/s41380-021-01175-1 [PubMed: 34127816]
51. Main, M.J., Cryan, J.E., Dupere, J.R., Cox, B., Clare, J.J., Burbidge, S.A., 2000. Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine.  Mol. Pharmacol. 58, 253–262. https://doi​.org/10.1124/mol.58.2.253 [PubMed: 10908292]
52. McMahon, J.J., Yu, W., Yang, J., Feng, H., Helm, M., McMahon, E., Zhu, X., Shin, D., Huang, Y., 2015. Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice.  Neurobiol. Dis. 73, 296–306. https://doi​.org/10.1016/j​.nbd.2014.10.004 [PMC free article: PMC4394017] [PubMed: 25315683]
53. Mitani, A., Komiyama, T., 2018. Real-Time Processing of Two-Photon Calcium Imaging Data Including Lateral Motion Artifact Correction.  Front. Neuroinformatics 12, 98. https://doi​.org/10.3389/fninf.2018.00098 [PMC free article: PMC6305597] [PubMed: 30618703]
54. Mouchati, P.R., Barry, J.M., Holmes, G.L., 2019. Functional brain connectivity in a rodent seizure model of autistic-like behavior.  Epilepsy Behav. EB 95, 87–94. https://doi​.org/10.1016/j​.yebeh.2019.03.046 [PMC free article: PMC7117868] [PubMed: 31030078]
55. Murphy, C.C., Trevathan, E., Yeargin-Allsopp, M., 1995. Prevalence of epilepsy and epileptic seizures in 10-year-old children: results from the Metropolitan Atlanta Developmental Disabilities Study.  Epilepsia 36, 866–872. https://doi​.org/10.1111/j​.1528-1157.1995.tb01629.x [PubMed: 7544279]
56. Musunuru, K., Chadwick, A.C., Mizoguchi, T., Garcia, S.P., DeNizio, J.E., Reiss, C.W., Wang, K., Iyer, S., Dutta, C., Clendaniel, V., Amaonye, M., Beach, A., Berth, K., Biswas, S., Braun, M.C., Chen, H.-M., Colace, T.V., Ganey, J.D., Gangopadhyay, S.A., Garrity, R., Kasiewicz, L.N., Lavoie, J., Madsen, J.A., Matsumoto, Y., Mazzola, A.M., Nasrullah, Y.S., Nneji, J., Ren, H., Sanjeev, A., Shay, M., Stahley, M.R., Fan, S.H.Y., Tam, Y.K., Gaudelli, N.M., Ciaramella, G., Stolz, L.E., Malyala, P., Cheng, C.J., Rajeev, K.G., Rohde, E., Bellinger, A.M., Kathiresan, S., 2021. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates.  Nature 593, 429–434. https://doi​.org/10.1038​/s41586-021-03534-y [PubMed: 34012082]
57. Ogiwara, I., Iwasato, T., Miyamoto, H., Iwata, R., Yamagata, T., Mazaki, E., Yanagawa, Y., Tamamaki, N., Hensch, T.K., Itohara, S., Yamakawa, K., 2013. Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome.  Hum. Mol. Genet. 22, 4784–4804. https://doi​.org/10.1093/hmg/ddt331 [PMC free article: PMC3820136] [PubMed: 23922229]
58. Ogiwara, I., Miyamoto, H., Morita, N., Atapour, N., Mazaki, E., Inoue, I., Takeuchi, T., Itohara, S., Yanagawa, Y., Obata, K., Furuichi, T., Hensch, T.K., Yamakawa, K., 2007. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation.  J. Neurosci. Off. J. Soc. Neurosci. 27, 5903–5914. https://doi​.org/10.1523/JNEUROSCI​.5270-06.2007 [PMC free article: PMC6672241] [PubMed: 17537961]
59. Olson, C.A., Vuong, H.E., Yano, J.M., Liang, Q.Y., Nusbaum, D.J., Hsiao, E.Y., 2018. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet.  Cell 174, 497. https://doi​.org/10.1016/j​.cell.2018.06.051 [PMC free article: PMC6062008] [PubMed: 30007420]
60. Packer, A.M., Peterka, D.S., Hirtz, J.J., Prakash, R., Deisseroth, K., Yuste, R., 2012. Two-photon optogenetics of dendritic spines and neural circuits.  Nat. Methods 9(12), 1202–1205. https://doi​.org/10.1038/nmeth.2249 [PMC free article: PMC3518588] [PubMed: 23142873]
61. Peñagarikano, O., Abrahams, B.S., Herman, E.I., Winden, K.D., Gdalyahu, A., Dong, H., Sonnenblick, L.I., Gruver, R., Almajano, J., Bragin, A., Golshani, P., Trachtenberg, J.T., Peles, E., Geschwind, D.H., 2011. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.  Cell 147, 235–246. https://doi​.org/10.1016/j​.cell.2011.08.040 [PMC free article: PMC3390029] [PubMed: 21962519]
62. Peñagarikano, O., Lázaro, M.T., Lu, X.-H., Gordon, A., Dong, H., Lam, H.A., Peles, E., Maidment, N.T., Murphy, N.P., Yang, X.W., Golshani, P., Geschwind, D.H., 2015. Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism.  Sci. Transl. Med. 7, 271ra8. https://doi​.org/10.1126/scitranslmed​.3010257 [PMC free article: PMC4498455] [PubMed: 25609168]
63. Poliak, S., Gollan, L., Martinez, R., Custer, A., Einheber, S., Salzer, J.L., Trimmer, J.S., Shrager, P., Peles, E., 1999. Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels.  Neuron 24, 1037–1047. https://doi​.org/10.1016​/s0896-6273(00)81049-1 [PubMed: 10624965]
64. Poliak, S., Gollan, L., Salomon, D., Berglund, E.O., Ohara, R., Ranscht, B., Peles, E., 2001. Localization of Caspr2 in myelinated nerves depends on axon-glia interactions and the generation of barriers along the axon.  J. Neurosci. Off. J. Soc. Neurosci. 21, 7568–7575. https://doi​.org/10.1523/JNEUROSCI​.21-19-07568.2001 [PMC free article: PMC6762895] [PubMed: 11567047]
65. Poliak, S., Salomon, D., Elhanany, H., Sabanay, H., Kiernan, B., Pevny, L., Stewart, C.L., Xu, X., Chiu, S.-Y., Shrager, P., Furley, A.J.W., Peles, E., 2003. Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1.  J. Cell Biol. 162, 1149–1160. https://doi​.org/10.1083/jcb.200305018 [PMC free article: PMC2172860] [PubMed: 12963709]
66. Poulin, J.-F., Caronia, G., Hofer, C., Cui, Q., Helm, B., Ramakrishnan, C., Chan, C.S., Dombeck, D.A., Deisseroth, K., Awatramani, R., 2018. Mapping projections of molecularly defined dopamine neuron subtypes using intersectional genetic approaches.  Nat. Neurosci. 21, 1260–1271. https://doi​.org/10.1038​/s41593-018-0203-4 [PMC free article: PMC6342021] [PubMed: 30104732]
67. Robinson, N.T.M., Descamps, L.A.L., Russell, L.E., Buchholz, M.O., Bicknell, B.A., Antonov, G.K., Lau, J.Y.N., Nutbrown, R., Schmidt-Hieber, C., Häusser, M., 2020. Targeted Activation of Hippocampal Place Cells Drives Memory-Guided Spatial Behavior. Cell 183, 1586–1599.e10. https://doi​.org/10.1016/j​.cell.2020.09.061 [PMC free article: PMC7754708] [PubMed: 33159859]
68. Rossignol, E., Kruglikov, I., van den Maagdenberg, A.M.J.M., Rudy, B., Fishell, G., 2013. CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures.  Ann. Neurol. 74, 209–222. https://doi​.org/10.1002/ana.23913 [PMC free article: PMC3849346] [PubMed: 23595603]
69. Satterstrom, F.K., Kosmicki, J.A., Wang, J., Breen, M.S., De Rubeis, S., An, J.-Y., Peng, M., Collins, R., Grove, J., Klei, L., Stevens, C., Reichert, J., Mulhern, M.S., Artomov, M., Gerges, S., Sheppard, B., Xu, X., Bhaduri, A., Norman, U., Brand, H., Schwartz, G., Nguyen, R., Guerrero, E.E., Dias, C., Betancur, C., Cook, E.H., Gallagher, L., Gill, M., Sutcliffe, J.S., Thurm, A., Zwick, M.E., Børglum, A.D., State, M.W., Cicek, A.E., Talkowski, M.E., Cutler, D.J., Devlin, B., Sanders, S.J., Roeder, K., Daly, M.J., Buxbaum, J.D., 2020. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.  Cell 180, 568–584.e23. https://doi​.org/10.1016/j​.cell.2019.12.036 [PMC free article: PMC7250485] [PubMed: 31981491]
70. Selimbeyoglu, A., Kim, C.K., Inoue, M., Lee, S.Y., Hong, A.S.O., Kauvar, I., Ramakrishnan, C., Fenno, L.E., Davidson, T.J., Wright, M., Deisseroth, K., 2017. Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice.  Sci. Transl. Med. 9. https://doi​.org/10.1126/scitranslmed​.aah6733 [PMC free article: PMC5723386] [PubMed: 28768803]
71. Shapiro, M.S., Roche, J.P., Kaftan, E.J., Cruzblanca, H., Mackie, K., Hille, B., 2000. Reconstitution of muscarinic modulation of the KCNQ2/KCNQ3 K(+) channels that underlie the neuronal M current.  J. Neurosci. Off. J. Soc. Neurosci. 20, 1710–1721. https://doi​.org/10.1523/JNEUROSCI​.20-05-01710.2000 [PMC free article: PMC6772928] [PubMed: 10684873]
72. Shuman, T., Aharoni, D., Cai, D.J., Lee, C.R., Chavlis, S., Page-Harley, L., Vetere, L.M., Feng, Y., Yang, C.Y., Mollinedo-Gajate, I., Chen, L., Pennington, Z.T., Taxidis, J., Flores, S.E., Cheng, K., Javaherian, M., Kaba, C.C., Rao, N., La-Vu, M., Pandi, I., Shtrahman, M., Bakhurin, K.I., Masmanidis, S.C., Khakh, B.S., Poirazi, P., Silva, A.J., Golshani, P., 2020. Breakdown of spatial coding and interneuron synchronization in epileptic mice.  Nat. Neurosci. 23, 229–238. https://doi​.org/10.1038​/s41593-019-0559-0 [PMC free article: PMC7259114] [PubMed: 31907437]
73. Stein, R.E., Kaplan, J.S., Li, J., Catterall, W.A., 2019. Hippocampal deletion of Na(V)1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet Syndrome.  Proc. Natl. Acad. Sci. U. S. A. 116, 16571–16576. https://doi​.org/10.1073/pnas.1906833116 [PMC free article: PMC6697805] [PubMed: 31346088]
74. Strauss, K.A., Puffenberger, E.G., Huentelman, M.J., Gottlieb, S., Dobrin, S.E., Parod, J.M., Stephan, D.A., Morton, D.H., 2006. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2.  N. Engl. J. Med. 354, 1370–1377. https://doi​.org/10.1056/NEJMoa052773 [PubMed: 16571880]
75. Sun, H., Takesian, A.E., Wang, T.T., Lippman-Bell, J.J., Hensch, T.K., Jensen, F.E., 2018. Early Seizures Prematurely Unsilence Auditory Synapses to Disrupt Thalamocortical Critical Period Plasticity.  Cell Rep. 23, 2533–2540. https://doi​.org/10.1016/j​.celrep.2018.04.108 [PMC free article: PMC6446922] [PubMed: 29847785]
76. Tai, C., Abe, Y., Westenbroek, R.E., Scheuer, T., Catterall, W.A., 2014. Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome.  Proc. Natl. Acad. Sci. U. S. A. 111, E3139–3148. https://doi​.org/10.1073/pnas.1411131111 [PMC free article: PMC4121787] [PubMed: 25024183]
77. Tatsukawa, T., Ogiwara, I., Mazaki, E., Shimohata, A., Yamakawa, K., 2018. Impairments in social novelty recognition and spatial memory in mice with conditional deletion of Scn1a in parvalbumin-expressing cells.  Neurobiol. Dis. 112, 24–34. https://doi​.org/10.1016/j​.nbd.2018.01.009 [PubMed: 29337050]
78. Tuchman, R., Alessandri, M., Cuccaro, M., 2010a. Autism spectrum disorders and epilepsy: moving towards a comprehensive approach to treatment.  Brain Dev. 32, 719–730. https://doi​.org/10.1016/j​.braindev.2010.05.007 [PubMed: 20558021]
79. Tuchman, R., Cuccaro, M., Alessandri, M., 2010b. Autism and epilepsy: historical perspective.  Brain Dev. 32, 709–718. https://doi​.org/10.1016/j​.braindev.2010.04.008 [PubMed: 20510557]
80. Tuchman, R., Rapin, I., 2002. Epilepsy in autism.  Lancet Neurol. 1, 352–358. https://doi​.org/10.1016​/s1474-4422(02)00160-6 [PubMed: 12849396]
81. Tuchman, R.F., Rapin, I., Shinnar, S., 1991. Autistic and dysphasic children.  II: Epilepsy. Pediatrics 88, 1219–1225. [PubMed: 1956740]
82. Vogt, D., Cho, K.K.A., Shelton, S.M., Paul, A., Huang, Z.J., Sohal, V.S., Rubenstein, J.L.R., 2018. Mouse Cntnap2 and Human CNTNAP2 ASD Alleles Cell Autonomously Regulate PV+ Cortical Interneurons.  Cereb. Cortex N. Y. N 1991 28, 3868–3879. https://doi​.org/10.1093/cercor/bhx248 [PMC free article: PMC6455910] [PubMed: 29028946]
83. Wang, H.S., Pan, Z., Shi, W., Brown, B.S., Wymore, R.S., Cohen, I.S., Dixon, J.E., McKinnon, D., 1998. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282, 1890–1893. https://doi​.org/10.1126/science​.282.5395.1890 [PubMed: 9836639]
84. Weckhuysen, S., Ivanovic, V., Hendrickx, R., Van Coster, R., Hjalgrim, H., Møller, R.S., Grønborg, S., Schoonjans, A.-S., Ceulemans, B., Heavin, S.B., Eltze, C., Horvath, R., Casara, G., Pisano, T., Giordano, L., Rostasy, K., Haberlandt, E., Albrecht, B., Bevot, A., Benkel, I., Syrbe, S., Sheidley, B., Guerrini, R., Poduri, A., Lemke, J.R., Mandelstam, S., Scheffer, I., Angriman, M., Striano, P., Marini, C., Suls, A., De Jonghe, P., 2013. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients.  Neurology 81, 1697–1703. https://doi​.org/10.1212/01​.wnl.0000435296.72400.a1 [PMC free article: PMC3812107] [PubMed: 24107868]
85. Weckhuysen, S., Mandelstam, S., Suls, A., Audenaert, D., Deconinck, T., Claes, L.R.F., Deprez, L., Smets, K., Hristova, D., Yordanova, I., Jordanova, A., Ceulemans, B., Jansen, A., Hasaerts, D., Roelens, F., Lagae, L., Yendle, S., Stanley, T., Heron, S.E., Mulley, J.C., Berkovic, S.F., Scheffer, I.E., de Jonghe, P., 2012. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy.  Ann. Neurol. 71, 15–25. https://doi​.org/10.1002/ana.22644 [PubMed: 22275249]
86. Willsey, A.J., Sanders, S.J., Li, M., Dong, S., Tebbenkamp, A.T., Muhle, R.A., Reilly, S.K., Lin, L., Fertuzinhos, S., Miller, J.A., Murtha, M.T., Bichsel, C., Niu, W., Cotney, J., Ercan-Sencicek, A.G., Gockley, J., Gupta, A.R., Han, W., He, X., Hoffman, E.J., Klei, L., Lei, J., Liu, W., Liu, L., Lu, C., Xu, X., Zhu, Y., Mane, S.M., Lein, E.S., Wei, L., Noonan, J.P., Roeder, K., Devlin, B., Sestan, N., State, M.W., 2013. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.  Cell 155, 997–1007. https://doi​.org/10.1016/j​.cell.2013.10.020 [PMC free article: PMC3995413] [PubMed: 24267886]
87. Wong, J.C., Shapiro, L., Thelin, J.T., Heaton, E.C., Zaman, R.U., D’Souza, M.J., Murnane, K.S., Escayg, A., 2021. Nanoparticle encapsulated oxytocin increases resistance to induced seizures and restores social behavior in Scn1a-derived epilepsy.  Neurobiol. Dis. 147, 105147. https://doi​.org/10.1016/j​.nbd.2020.105147 [PMC free article: PMC7726060] [PubMed: 33189882]
88. Yu, F.H., Mantegazza, M., Westenbroek, R.E., Robbins, C.A., Kalume, F., Burton, K.A., Spain, W.J., McKnight, G.S., Scheuer, T., Catterall, W.A., 2006. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy.  Nat. Neurosci. 9, 1142–1149. https://doi​.org/10.1038/nn1754 [PubMed: 16921370]
89. Yu, T.W., Chahrour, M.H., Coulter, M.E., Jiralerspong, S., Okamura-Ikeda, K., Ataman, B., Schmitz-Abe, K., Harmin, D.A., Adli, M., Malik, A.N., D’Gama, A.M., Lim, E.T., Sanders, S.J., Mochida, G.H., Partlow, J.N., Sunu, C.M., Felie, J.M., Rodriguez, J., Nasir, R.H., Ware, J., Joseph, R.M., Hill, R.S., Kwan, B.Y., Al-Saffar, M., Mukaddes, N.M., Hashmi, A., Balkhy, S., Gascon, G.G., Hisama, F.M., LeClair, E., Poduri, A., Oner, O., Al-Saad, S., Al-Awadi, S.A., Bastaki, L., Ben-Omran, T., Teebi, A.S., Al-Gazali, L., Eapen, V., Stevens, C.R., Rappaport, L., Gabriel, S.B., Markianos, K., State, M.W., Greenberg, M.E., Taniguchi, H., Braverman, N.E., Morrow, E.M., Walsh, C.A., 2013. Using whole-exome sequencing to identify inherited causes of autism.  Neuron 77, 259–273. https://doi​.org/10.1016/j​.neuron.2012.11.002 [PMC free article: PMC3694430] [PubMed: 23352163]