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Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies. 5th edition. New York: Oxford University Press; 2024. doi: 10.1093/med/9780197549469.003.0011
Abstract
Optogenetics rests on the activation of light-gated ion channels or pumps in transgenic animals, and it is used to reversibly excite or silence specific neuronal populations, with millisecond precision and with a higher spatial accuracy than electrical stimulation. To date, epilepsy researchers have used optogenetics to study this neurological disorder, and in particular focal seizures that originate from a discrete brain area as in mesial temporal lobe epilepsy. Here, we will review findings obtained by employing optogenetics in in vitro and in vivo models of focal epileptiform synchronization. We will also address the use of this technique to control acute and chronic spontaneous seizures induced by the administration of chemoconvulsants in animal models of mesial temporal lobe epilepsy, such as the kainic acid and the pilocarpine model. These findings reveal that optogenetic activation or inhibition of excitatory or inhibitory cells can exert paradoxical effects on seizure occurrence depending on the frequency and timing of light stimulation, as well as on the targeted neuronal populations. We also consider the limitations associated with the use of optogenetics and the potential issues that must be solved before this approach is translated to human application. We conclude that optogenetics, despite some limitations, represents an innovative and promising approach to improve our understanding of brain function in health and disease.
Introduction
Mesial temporal lobe epilepsy (MTLE) is the most common type of focal refractory epilepsy in adults and is characterized by spontaneous, recurring seizures arising from the hippocampus, rhinal cortices, or amygdala (Bartolomei et al., 2005; Engel, 1996; Gloor, 1997). Focal seizures often start to occur in MTLE patients in adulthood, many years after an initial brain insult such as status epilepticus (SE), traumatic brain injury, or encephalitis (de Lanerolle et al., 2003; French et al., 1993; Mathern et al., 2002; Salanova et al., 1994). MTLE patients present with a high incidence of cornu ammonis (CA) sclerosis, that is, atrophy that mirrors neuronal loss and gliosis in the Sommer’s sector (subiculum-CA1 transition zone), CA3 subfield, and endfolium (dentate hilus) (Engel et al., 2008; Gloor, 1997; Mathern et al., 1997).
Although several antiepileptic drugs are available to control seizures, up to one-third of MTLE patients show pharmacologically refractory seizures (Jallon, 1997). Surgical resection of the epileptic tissue often remains the only therapeutic alternative, although it cannot always be implemented (Engel et al., 2012; Salanova et al., 1994; Wiebe et al., 2001). Therefore, it is critical to identify the cellular and network pathological activity that leads to focal seizure generation in MTLE patients. Moreover, acquiring such knowledge may help to develop procedures that can be used to halt the changes in neuronal excitability leading to the chronic epileptic conditions; this process is known as epileptogenesis (Pitkänen & Sutula, 2002).
To understand MTLE pathophysiology and to develop new therapeutic approaches, animal models reproducing the electroencephalographic, behavioral, and neuropathological features of this epileptic disorder have been developed over the last four decades. One of these models uses kainic acid (a cyclic analog of L-glutamate and thus an agonist of glutamatergic receptors); local or systemic injections of kainic acid in rodents induce SE, followed a few days or weeks later by spontaneous seizures and neuropathological lesions that are similar to those occurring in most MTLE patients (Ben-Ari et al., 1979; Ben-Ari & Lagowska, 1978; Cavalheiro et al., 1982). The other model employs pilocarpine, a cholinergic muscarinic agonist; when administered systemically in rodents, pilocarpine induces a SE that is followed a few days to weeks later by spontaneous recurring seizures (Curia et al., 2008; Lévesque et al., 2021; Turski et al., 1989; Turski et al., 1983). Focal epileptiform discharges can also be studied with electrical kindling (see, for review, Morimoto et al., 2004); in this model, repeated electrical stimulation of the amygdala or hippocampus triggers focal seizures of increasing severity and duration. Finally, acute administration of compounds such as the K+ channel blocker 4-aminopyridine (4AP) or, to a lesser extent, GABAA receptor antagonists (such as pentylenetetratozol, picrotoxin [PTX], or bicuculine) have been used to study ictogenesis (Avoli & de Curtis, 2011). Such pharmacological procedures induce electrographic epileptiform events in in vitro preparations (e.g., tissue cultures, brain slices, isolated brains) as well as interictal and ictal activity associated with behavioral seizures in in vivo models. However, at the best of our knowledge, spontaneous “chronic” seizures do not continue to occur in these experiments once the initial pharmacological insult ends.
In the last two decades, epileptologists have employed optogenetics, an approach that combines the use of optics and genetics to activate light-gated ion channels or pumps (Deisseroth, 2011; Deisseroth et al., 2006), to control neuronal network activity and thus to identify the pathological mechanisms that lead to ictogenesis in in vitro and in vivo models of MTLE (Cela & Sjöström, 2019; Kokaia et al., 2013; Krook-Magnuson, Ledri, et al., 2014; Shiri et al., 2015, 2016, 2017; Sørensen & Kokaia, 2013; Tønnesen et al., 2009; Tønnesen & Kokaia, 2017). Most optogenetic studies in the field of epilepsy have used specific types of transfected cells that express rhodopsins (which contain an opsin protein and a light-sensitive chromophore); these rhodopsins, when activated by light at specific wavelengths, can cause either depolarization or hyperpolarization of the cell membrane resulting in neuronal excitation or silencing, respectively (Ferenczi et al., 2019). Commonly used rhodopsins are channelrhodopsins (ChR2), halorhodopsins (NpHR), and archaerhodopsins (Arch) (Boyden et al., 2005; Chow et al., 2010; Yizhar et al., 2011). Optogenetics represents a valuable tool to modulate focal seizures (Tønnesen & Kokaia, 2017), and it provides, compared to electrical stimulation, the advantage of controlling the excitability of specific, targeted cell populations in seizure-onset zones as well as in remote brain structures.
In this chapter, we will review studies that have used optogenetics to establish the dynamics of interictal and ictal discharges in in vitro and in in vivo models of epileptiform synchronization; in the latter cases optogenetics was employed to modulate spontaneously occurring seizures. We will also discuss issues that should be addressed before optogenetic procedures are used to treat focal seizures in epileptic patients.
Optogenetic Stimulation in In Vitro Models of Epileptiform Synchronization
One of the first studies to employ optogenetics was performed by Tønnesen et al. (2009) in an in vitro model of epileptiform synchronization; they found that optogenetic hyperpolarization of CA3 NpHR-expressing principal cells (cf. Zhang et al., 2007) shortens the duration of paroxysmal depolarizing shifts induced by electrical stimulation: paroxysmal depolarizing shifts are the intracellular counterpart of interictal spikes (see Chapter 1, this volume). According to these authors, hyperpolarizing principal cells through optogenetic activation was sufficient to control epileptiform synchronization in the hippocampus, even when inhibition was compromised by antagonizing GABAA receptor signaling with PTX. This evidence was later confirmed by Berglind et al. (2014), who analyzed the epileptiform activity generated in vitro by NpHR3.0-expressing hippocampal slices during perfusion of medium containing low Mg2+ artificial cerebrospinal fluid (ACSF), 4AP, and the GABAA receptor blocker PTX. These experiments revealed that steady (30–60 s) optogenetic hyperpolarization of principal cells markedly reduced epileptiform discharges, thus confirming the hypothesis that silencing of principal cells is sufficient to control epileptiform synchronization.
Around the same time, employing the 4AP in vitro model, Chiang et al. (2014) reported that high-frequency optogenetic activation at 20 Hz of ChR2-expressing excitatory and inhibitory neurons in the hippocampus suppresses epileptiform activity. However, since ChR2 in these animals was mostly expressed in interneurons, these authors proposed that the control of epileptiform discharges was mainly due to enhanced inhibition. Accordingly, epileptiform discharges were no longer suppressed by optogenetic stimulation when hippocampal slices were bathed in 4AP + PTX. These findings led them to conclude that, as previously reported by Berglind et al. (2014), optogenetic activation of interneurons suppresses 4AP-induced epileptiform activity through hyperpolarization of principal cells. A massive light-induced release of GABA from ChR2-expressing interneurons also occurs with 20 Hz and 50 Hz optogenetic stimulation, which hyperpolarizes principal cells and inhibits epileptiform activity in zero-Mg2+ ACSF containing 4AP (Ledri et al., 2014). Activating different populations of interneurons was, however, more efficient in inhibiting principal cells and in inducing anti-ictogenic effects in this in vitro model, compared to what was obtained with the activation of parvalbumin (PV)-positive or somatostatin (SOM)-positive interneurons alone (Ledri et al., 2014).
Further evidence have, however, revealed that optogenetic activation of interneurons and thus increased inhibition can also favor ictogenesis (Bohannon & Hablitz, 2018; M. Chang et al., 2018; Sessolo et al., 2015; Shiri et al., 2015, 2016; Yekhlef et al., 2015); such paradoxical effects presumably mirror a massive activation of postsynaptic GABAA receptors (see, for review, de Curtis & Avoli, 2016 and Di Cristo et al., 2018). These findings were first reported by Yekhlef et al. (2015), who found that during 4AP application, light stimulation of ChR2-expressing PV-positive interneurons and ChR2-expressing SOM-positive interneurons in the medial entorhinal cortex induces interictal and ictal discharges that are similar to those occurring spontaneously. Interestingly, in this study, optogenetically-induced preictal spikes were accompanied by large increases in extracellular K+ concentration, similar to what was previously reported by Avoli et al. (1996). It has been proposed that these elevations in extracellular K+ rest on excessive GABAergic signaling, which leads to intracellular Cl− accumulation and subsequent activity of the KCl cotransporter 2 (KCC2) that extrudes both Cl− and K+ from the intracellular compartment (Viitanen et al., 2010); these elevations in extracellular K+ depolarize neighboring neurons, thus triggering ictal discharges (see, for review, Avoli & de Curtis, 2011; de Curtis & Avoli, 2016; Di Cristo et al., 2018, see also Chapter 6, this volume).
Ictal discharges induced by 4AP in vitro are often similar to low-voltage, fast-onset (LVF) seizures that are observed in in vivo animal models of MTLE (Behr et al., 2017; Bragin et al., 2005; Gnatkovsky et al., 2008; Lévesque et al., 2012, 2019; Li et al., 2019; Xu et al., 2016) and in MTLE patients (Elahian et al., 2018; Ogren et al., 2009; Perucca et al., 2013; Singh et al., 2015). These seizures are characterized by the occurrence of a positive- or negative-going spike followed by low-amplitude high-frequency activity and are thought to be mediated by the preponderant involvement of GABAergic-mediated inhibitory transmission (Avoli et al., 2016). In line with this view, optogenetic activation of PV- or SOM-positive interneurons in the 4AP in vitro model can trigger ictal discharges with an LVF pattern (Shiri et al., 2015, 2016; Yekhlef et al., 2015) (Fig. 11–1Aa and b). The second pattern of seizure onset seen in MTLE patients, termed hypersynchronous-onset seizures (HYP), is characterized at onset by a pattern of focal (preictal) spiking at a frequency of ~2 Hz. These seizures are thought to depend on the interaction between excitatory and inhibitory cells (Avoli et al., 2016; Kohling et al., 2016) and are triggered in the 4AP in vitro model by the activation of CAMKII-positive principal cells (Fig. 11–1Ba and b) (Shiri et al., 2016). They are also observed in animal models of MTLE (Behr et al., 2017; Bragin et al., 2005; Lévesque et al., 2012, 2019; Li et al., 2019; Xu et al., 2016) and in epileptic patients (Memarian et al., 2015; Ogren et al., 2009; Perucca et al., 2013; Velasco et al., 2000). Further experiments carried out by Yekhlef et al. (2017) demonstrated that ictal discharges in the 4AP in vitro model can also be triggered by optogenetic activation of principal cells in the entorhinal cortex. Such epileptiform activity was strongly reduced by the GABAA receptor antagonist gabazine; therefore, these investigators concluded that epileptiform activity requires intact GABAergic transmission to be generated.

Figure 11–1.
Findings obtained in the in vitro 4AP model of epileptiform synchronization. In these experiments field recordings and optogenetic stimuli were made in the mouse EC. A. During 4AP application low-voltage, fast (LVF) ictal discharges can occur spontaneously (more...)
Epileptiform discharges in the 4AP model can be initiated not only by a series of repetitive light pulses (Shiri et al., 2015, 2016; Yekhlef et al., 2015) but also with single and brief (3–30 ms) optogenetic activation of ChR2-expressing GABAergic interneurons (Chang et al., 2018). These brief optogenetic stimulations trigger an initial hyperpolarization of principal cells that is followed by postinhibitory rebound spikes and a subsequent depolarization leading to the transition to ictal activity (Chang et al., 2018). In brain tissue obtained from patients that underwent surgery for the treatment of refractory epilepsy, short puffs of GABA also initiate ictal events under 4AP (Chang et al., 2018). Overall, these findings emphasize that the synchronous interneuronal firing serves as a trigger that initiates a cascade of events that lead and presumably sustain ictal activity. A similar stimulation protocol (0.5 to 2.5 ms light pulses), which was used to excite ChR2-expressing mossy cells in the dentate gyrus cells of transgenic mice in vitro, can trigger epileptiform activity in CA3, CA1, and subiculum (Botterill et al., 2019).
In the subiculum of CamKIIa-ChR2 mice, optogenetic activation of principal neurons, but not of PV interneurons in PV-ChR2 mice, can induce epileptiform activity, which is reduced by the GABAA receptor antagonist PTX (Wickham et al., 2023). As illustrated in Figure 11–2A, light-induced epileptiform discharges (LIEDs)—characterized by an initial ictaform activity that is followed by interictal events—are generated by subicular principal neurons recorded with whole-cell patch-clamp technique in the presence of ACSF containing 4AP.

Figure 11–2.
Optogenetic stimulation of principal neurons in CamKIIa-ChR2 subiculum induces GABAA signaling-dependent epileptiform discharges. A. Whole-cell recording from a subicular principal cell during optogenetic stimulation in the presence of 4AP. Note that (more...)
However, when GABAA receptor antagonist PTX is added to the perfusion medium, the ictaform response disappears while interictal events persist (Fig. 11–2B). Further addition of D-APV and NBQX in the perfusion medium eliminates single paroxysmal depolarizing shifts in the principal neurons remaining after PTX application (Fig. 11–2C and D), suggesting that the latter were generated by glutamatergic synaptic connections. Thus, it can be concluded that, in the presence of 4AP, selective optogenetic stimulation of subicular principal neurons can induce LIEDs by downstream synaptic activation of GABAergic interneurons, which then via inhibitory feedback afferents to principal cells creates an oscillatory loop, maintaining the epileptiform activity. Results on the percentage of cells exhibiting LIEDs in the medium containing 4AP + PTX compared to 4AP only are summarized in Figure 11–2E.
It has also been reported that low-frequency (1 Hz) optogenetic activation of either interneurons or principal cells can reduce the rate of occurrence of 4AP-induced ictal discharges (Shiri et al., 2017). As illustrated in Figure 11–1C, 1 Hz optogenetic activation of SOM-positive interneurons transiently abolishes spontaneously occurring 4AP-induced ictal discharges. Similar results were obtained with 1 Hz stimulation of calcium/calmodulin-dependent protein kinase II (CaMKII)-positive principal cells and of PV-positive interneurons (Fig. 11–1D). It is important to note how optogenetic stimulation of CamKII-positive principal cells was associated with a larger field response compared to when PV- or SOM-positive interneurons were stimulated (not shown) and to a longer lasting anti-ictogenic effect once stimulation was stopped (Fig. 11–1E). Therefore, more prominent anti-ictogenic effects are associated with CaMKII-positive principal cell activation as compared to interneuron activation; these findings may result from the post-spike depression in excitability that follows synchronous events generated by the activation of glutamatergic neuronal networks.
Optogenetic Stimulation in In Vivo Models of Mesial Temporal Lobe Epilepsy
Acute Seizures
High-frequency optogenetic stimulation (20–50 Hz) of ChR2-expressing cells (which are mainly interneurons) in the CA3 region of the hippocampus can also suppress seizures induced by 4AP in vivo (Chiang et al., 2014). Interestingly, the anti-ictogenic effects caused by unilateral optogenetic stimulation suppresses seizures in both the ipsilateral and contralateral hippocampus, indicating that the optogenetic activation of one hippocampus can prevent seizure generalization by preventing the recruitment of neurons at distal sites. Chiang et al. (2014) also found that the suppressive effect on seizures decreases over time with continuous stimulation (lasting more than 10 s), but significantly improves when intermittent optogenetic stimulation is used (i.e., when the interval between stimulation epochs is longer than 3 s). According to these authors, the anti-ictogenic effects associated with the optogenetic activation of ChR2-expressing interneurons should be attributed to the increased GABAergic inhibition and thus to the hyperpolarization of principal cells (Chiang et al., 2014). Later, anti-ictogenic effects were also reported to occur with the optogenetic activation of ChR2-expressing PV-positive interneurons at 50–100 Hz in the thalamic nucleus reticularis in animals that were treated with concomitant cortical application of 4AP and electrical stimulation of the corpus callosum (Chang et al., 2017). Similar results were observed in animals in which acute seizures were induced with a local application of bicuculline in the piriform cortex or with amygdala kindling; optogenetic activation of GABAergic interneurons in the nucleus reticularis was therefore associated with anti-ictogenic effets (Wicker & Forcelli, 2021).
Anti-ictogenic effects have also been reported with low-frequency (1 Hz) optogenetic stimulation of Thy1-ChR2-expressing excitatory and inhibitory cells close to the site of 4AP injection in the hippocampus; such procedure induced a decrease in seizure rate of ~70% (Ladas et al., 2015). Moreover, these investigators found that the anti-ictogenic effects induced with low-frequency stimulation are observed in both the ipsi- and contralateral hippocampus, as it was previously observed by Chiang et al. (2014) with high-frequency stimulation procedures. The same protocol of low-frequency stimulation, when applied to VGAT-ChR2 transgenic mice, has revealed that 1 Hz activation of interneurons induces a more rapid anti-ictogenic effect in both ipsi- and contralateral hippocampus compared to what was obtained by activating both excitatory and inhibitory cells. However, the anti-ictogenic effects associated with the activation of interneurons diminished over time, whereas the activation of excitatory and inhibitory cells in Thy1-ChR2 transgenic mice improved as stimulation persisted (Ladas et al., 2015).
Isolated, short-lasting light pulses employed to activate ChR2-expressing GABAergic interneurons also reduce seizure rates in awake animals treated with a local application of 4AP in the somatosensory cortex (Chang et al., 2018). However, in line with the findings reported by Chiang et al. (2014), this phenomenon appeared to depend on the interval between stimulations; accordingly, when the interstimulus interval was set at 300 ms, the efficiency of optogenetic stimulation in suppressing seizures was 83%, compared to 14% when the interval between stimulation was set to 50 s.
Lu et al. (2016) analyzed the anti-ictogenic effects induced by high-frequency optogenetic stimulation (130 Hz for 60 s) of ChR2-expressing GABAergic interneurons in the dorsal hippocampus, and they found that kainic acid-induced, acute seizures are suppressed by optogenetic activation of GABAergic interneurons. Moreover, such stimulation procedure decreased the synchrony between different brain regions such as the dentate gyrus and the entorhinal cortex or dentate gyrus and the primary motor cortex. In line with the findings of Chang et al. (2018) and Chiang et al. (2014), Lu et al. (2016) reported that intermittent stimulation of ChR2-expressing GABAergic interneurons (1 min ON and 5 min OFF) induces a strong anti-ictogenic action; these effects increased over time and were associated with a significant decrease in seizure-induced cFos expression in the dentate gyrus, thus suggesting that neuronal excitability is decreased in hippocampal structures during optogenetic stimulation of ChR2-expressing GABAergic interneurons.
In the lithium-pilocarpine epilepsy model, light stimulation of halorhodopsin (eNphR)-expressing hippocampal principal cells (2 min ON and 3 min OFF) delays the electrographic and behavioral onset of spontaneous seizures (Sukhotinsky et al., 2013). Moreover, inhibition of principal cells in the hippocampus changes seizure dynamics, since it delays the development of high-amplitude ictal activity. In line with the evidence obtained by Chiang et al. (2014) and Ladas et al. (2015) with 4AP, unilateral activation of one hippocampus in the lithium-pilocarpine model is sufficient to prevent seizure propagation and to decrease behavioral symptoms.
However, as shown in several in vitro studies (Botterill et al., 2019; Chang et al., 2018; Shiri et al., 2015, 2016; Yekhlef et al., 2015), optogenetic stimulation of excitatory or inhibitory cells can also induce pro-ictogenic effects in in vivo experiments. Light pulses to activate Thy1-ChR2-expressing cells (which include principal cells and interneurons) in the hippocampus of anesthetized animals triggers ictal discharges that are time-locked to optogenetic stimulations as well as spontaneous ictal events that occur between light pulses in both the ipsilateral and contralateral hemisphere (Berglind et al., 2018). Further experiments by this group, however, revealed that inhibiting with chemogenetics the contralateral hippocampus by hyperpolarizing CamKII-expressing mice could counteract the progressive intensification of ictal discharges (Berglind et al., 2018).
Similar pro-ictogenic effects have been reported with optogenetic activation of PV-positive interneurons, which is in line with the hypothesis that the activation of GABAergic interneurons can foster ictogenesis. Chang et al. (2018) have demonstrated that brief (30 ms) optogenetic stimulation of VGAT-ChR2-positive GABAergic interneurons in transgenic mice treated with a local application of 4AP in the superficial layer (2/3) of the somatosensory cortex triggers seizures. More recently, Magloire et al. (2019) have reported that although 10 s of optogenetic stimulation of PV-positive interneurons shortens the duration of pilocarpine-induced acute seizures in the primary visual cortex, it can increase seizure duration when optogenetic stimulation is performed later than 2 s after ictal onset. These paradoxical effects were attributed to the potassium-chloride co-transporter KCC2, since its overexpression in principal cells did not prevent the anti-ictogenic effect associated with the activation of PV-positive interneurons at seizure onset but abolished the proictal effects exerted by delayed stimulation. Therefore, these investigators concluded that the limited ability of principal neurons to resist Cl− loading during excessive network activity contributes to the seizure-promoting action of PV-positive interneurons (Magloire et al., 2019). This evidence indicates that in epileptic patients, the administration of benzodiazepines (which enhance GABAA-receptor mediated signaling) could potentially exacerbate pathological network synchronization (Chang et al., 2018; Raimondo & Dulla, 2019).
Spontaneous Seizures
The chronic epileptic condition that develops a few days or weeks after SE in the pilocarpine and kainic acid models of MTLE is characterized by interictal spikes and seizures that, as reported in epileptic patients, are often resistant to anti-epileptic drugs (Chakir et al., 2006; Glien et al., 2002; Lévesque et al., 2015). Spontaneous seizures occurring in kainic acid-treated mice can be halted by inhibiting CaMKII-eNpHR expressing excitatory principal cells in the hippocampus when light pulses are delivered at seizure onset (50–2000 ms light pulses, 50–100 ms OFF, for 30–60 s) (Krook-Magnuson et al., 2013). Similar results were obtained with the activation of ChR2-expressing PV-positive GABAergic interneurons, even if optogenetic stimulation was performed in the hippocampus contralateral to the injected hippocampus (Krook-Magnuson et al., 2013). Interestingly, optogenetic activation of PV-positive interneurons in the hippocampus of kainic acid-treated animals also improved performance in cognitive tasks (Kim et al., 2020). It is important to note how seizure duration is also reduced with the activation of mossy cells in the dentate gyrus contralateral to the kainic acid-injected hippocampus (20 Hz for 15 s) (Bui et al., 2018).
Another study performed by Krook-Magnuson et al. (2014) investigated whether optogenetic activation of remote brain regions, such as the cerebellum, can provide seizure control; the cerebellum is anatomically and functionally connected to the hippocampus (Watson et al., 2018) and modulates hippocampal function during cognitive tasks (Zeidler et al., 2020). They found that optogenetic excitation or inhibition of PV-expressing Purkinje cells in the lateral or midline cerebellum (1000 ms light pulses, 50 ms OFF, for 3 s) of kainic acid-treated animals during the chronic period shortens seizure duration; however, a reduction in seizure frequency occurred only when PV-positive cells in the midline cerebellum were activated. These findings indicated that the cerebellum could be a potential therapeutic target for the treatment of focal seizures (cf. Cooper, 1974). It remains, however, unclear through which mechanisms cerebellar optogenetic stimulation controls hippocampal seizures, since both excitation and inhibition of cerebellar Purkinje cells decreased seizure duration (Krook-Magnuson et al., 2014).
Since Purkinje cells in the vermis inhibit neurons in the fastigial nucleus, Streng and Krook-Magnuson (2020) investigated later whether seizure control in the kainic acid model could be achieved through optogenetic modulation of neurons in this region. Inhibiting VGluT2-HR-expressing neurons in the fastigial nucleus (1000 ms light pulses, 50 ms OFF, for 3 s) did not induce any significant effects, but excitation of VGluT2-ChR2-expressing neurons in this area halted hippocampal seizures, independently of whether stimulation was performed in the fastigial nucleus that was ipsilateral or contralateral to the injected hippocampus. Therefore, these findings emphasize the role of the cerebellum in the modulation of hippocampal seizures, but more specifically of fastigial nucleus excitation.
The role of remote network involvement has also been demonstrated in “optogenetic kindling” in anaesthetized animals. As illustrated in Figure 11–3A, the progressive intensification of after-discharges induced by optogenetic stimulation of principal neurons in one hippocampus was suppressed by chemogenetic inhibition of the contralateral hippocampus (Fig. 11–3A and B, blue lines) (Berglind et al., 2018). Optogenetic stimulation of the hippocampus by implanted optical fiber in CamKIIa-ChR2 mice with rapid kindling protocol (40 train stimulations, 5 min apart) induced progressive intensification of afterdischarges in duration (Fig. 11–3A and B, blue lines). This progressive intensification of afterdischarges was abolished when contralateral hippocampus was inhibited by chemogenetics (Fig. 11–3A and B, red lines, arrow). For the chemogenetic inhibition, contralateral hippocampus is injected by an AAV vector carrying gene for hM4DGi, an inhibitory DREADD (designer receptor activated by designer drug). Intraperitoneal injection of the specific ligand (clozapine N-oxide; CNO) for this receptor selectively activates hM4DGi and hyperpolarizes neurons, thus inhibiting their activity (schematically shown on Fig. 11–3D by the yellow-colored neurons).

Figure 11–3.
Inhibiting contralateral hippocampus via activation of hM4D blocks afterdischarge development induced by optogenetic train stimulation in CaMKIIa-ChR2 mice. A. Quantification of afterdischarge (AD) durations, which were remarkably similar between ipsilateral (more...)
The results and conclusions of these experiments are summarized by a cartoon in Figure 11–3C: repetitive unilateral optogenetic stimulation of the hippocampus leads to generation of afterdischarges which spread to the contralateral dentate gyrus (Fig. 11–3C, red arrow), thus creating a transhemispheric feedback loop (Fig. 11–3C, black arrow) leading to progressive intensification of afterdischarges bilaterally. Abolishing the feedback from the contralateral dentate gyrus by CNO halts the progression of optogenetic kindling (schematically indicated on Fig. 11–3D as yellow color of affected neurons and a dotted line). These data also support the idea of widespread network involvement in epileptogenesis and ictogenesis, and they open the door for alternative focal treatment strategies, outside the seizure origin area in case it is located in eloquent region.
Paschen et al. (2020) have recently reported that the frequency of optogenetic stimulation has different effects on spontaneous seizures in the kainic acid model; they found that low-frequency optogenetic stimulation (1 Hz) of CamKII-positive principal cells in the entorhinal cortex has anti-ictogenic properties, whereas stimulation at 10 Hz induces seizures. These pro-ictogenic effects were, however, prevented when the pro-ictogenic 10 Hz stimulation protocol was preceded by a 30 min period of 1 Hz stimulation. According to these authors, optogenetic low-frequency stimulation of entorhinal cortex afferents leads to glutamatergic synaptic perturbation, followed by a transient suppression of neuronal activity that interferes with the recurrent generation of epileptiform activity. Such reduction in excitability could be similar to what occurs after interictal spikes (de Curtis et al., 2001) that, according to some studies, may have an anti-ictogenic role in epilepsy (Avoli, 2001; Avoli et al., 2006).
More recently, Chen et al. (2021) have targeted with optogenetics hippocampal PV-interneurons expressing ChRmine, a red-shifted opsin that exhibits large photocurrents and high sensitivity to light stimulation (Marshel et al., 2019), which renders neurons expressing these opsins sensitive to transcranial optogenetic stimulation. Using the intra-hippocampal kainic acid model, Chen et al. (2021) performed on-demand transcranial optogenetic stimulation of these ChRmine-expressing PV-positive interneurons during the chronic period. Optogenetic stimulation after seizure onset induced a 51% decrease in seizure duration compared to sham treatment. Activating PV-positive interneurons was more efficient in stopping seizures since activating other types of hippocampal interneurons only reduced seizure duration by 27% compared to sham treatment. These findings demonstrate that optogenetic modulation of focal seizures could be achieved less invasively without any disruption of brain tissue induced by transcranial surgery.
To date, few studies have analyzed the effects of optogenetic stimulation on spontaneous seizures in the pilocarpine model of MTLE. Since spontaneous seizures in this model often start from the hippocampus (Behr et al., 2017; Lévesque et al., 2012; Toyoda et al., 2013), Lévesque et al. (2019) investigated whether unilateral continuous optogenetic stimulation of ChR2-expressing PV-positive interneurons (30 s light trains at 8 Hz every 2 min for 14 days) in the CA3 subfield (Fig. 11–4A) decreases seizure rates in pilocarpine-treated mice. Although the proportion of nonconvulsive and convulsive seizures was similar between control and stimulated groups (Fig. 11–4B), PV-ChR2 animals presented with lower rates of spontaneous seizures compared to PV-Cre animals (Fig. 11–4C). Rates of interictal spikes were also significantly lower in the PV-ChR2 group compared to the PV-Cre group (Fig. 11–4D), as well as rates of interictal spikes with fast ripples (Fig. 11–4E and F) and of isolated fast ripples (Fig. 11–4G and H). These findings are in line with the evidence obtained by Krook-Magnuson et al. (2013), who could reduce the occurrence of seizures in the kainic acid model by using closed-loop activation of PV-positive interneurons. However, Lévesque et al. (2019) also found that the “residual” seizures could be triggered during optogenetic stimulation (Fig. 11–4I and J), which is in keeping with what was reported in vitro with optogenetics (Botterill et al., 2019; Chang et al., 2018; Shiri et al., 2015, 2016; Yekhlef et al., 2015) and in line with what was obtained in vivo using single-unit recordings in pilocarpine-treated animals, namely that PV interneurons could play significant roles in the transition from an interictal to an ictal state (Miri et al., 2018). According to these findings, in pilocarpine-treated epileptic mice, activation of PV-positive interneurons—and thus increased inhibition—provides an overall antiseizure effect while playing, paradoxically, a pro-ictogenic role once limbic network excitability reaches a suitable condition for generating seizures.

Figure 11–4.
The paradoxical effects of PV-positive interneuron stimulation in the pilocarpine model of mesial temporal lobe epilepsy. A. Schematic diagram showing the location of the optic fiber and bipolar electrode in the CA3 region of the hippocampus. The optic (more...)
Limitations and Clinical Translation of Optogenetic Procedures
A main advantage of optogenetics is that it can be used to exert a rapid, reversible, and bidirectional (i.e., activation or inhibition) control of neuronal activity; however, this technique has some limitations (see, for review, Kokaia et al. 2013; White et al. 2020). First, light activation of opsins has an impact not only on specific cell types but also affects widespread neuronal networks to which these cells project (Kokaia et al., 2013). For instance, GABAergic interneurons in the hippocampus have long-range projections to the subiculum, septum, and cortex (Jinno et al., 2007), and thus they control neuronal network oscillations and interactions between multiple brain regions (Buzsáki & Chrobak, 1995). Optogenetic stimulation of these GABAergic neurons would therefore not only modulate hippocampal activity but also the activity of remote brain regions. This phenomenon could explain why unilateral stimulation of PV-interneurons often suppresses seizures in both the ipsi and contralateral hemisphere (Berglind et al., 2018; Chiang et al., 2014; Krook-Magnuson et al., 2013; Ladas et al., 2015). Moreover, opsins may leak current without light, leading to spontaneous activity, or build up within cells, causing toxicity over time (Rossi et al., 2015). In addition, excessive activation of opsin, such as eNpHR, may alter chloride homeostasis and lead to aberrant activating, instead of inhibiting effects on the neurons, as it has been demonstrated by Sørensen et al. (2017)
Before using optogenetics to control seizures in humans, several issues must also be addressed. We have to acquire more knowledge on the long-term consequence of opsin expression and on the safety and efficiency of viral vectors (Delbeke et al., 2017; White et al., 2020). Long-term exposure to light stimulation can also induce change in the morphology of cells and a reduced neuronal response over time (Delbeke et al., 2017), and it is unknown whether insertion of a retrovirus into the genome of neurons leads to expression of nonhuman opsin proteins (White et al., 2020). Such mutagenesis could also result in tumor formation (White et al., 2020). Moreover, implantation of optrodes and the heat generated by continuous or frequent light stimulation can induce neuronal damage and disrupt the blood–brain barrier (Delbeke et al., 2017). The human immune response to the administration of viral vectors could also compromise the activation of opsins with light; accordingly, a recent study has demonstrated that ChR2 immunogenicity in the spinal cord induces a loss of opsin expression and death of ChR2-expression axons, resulting in denervation atrophy of the corresponding muscle (Maimon et al., 2018). Finally, although optogenetic activation of specific cell types is efficiently used in animals with small brains, it is unclear whether such a method would induce similar effects in humans with large brain volume. The volume of cell transduction and illumination must be sufficiently large to activate or inhibit neuronal populations in the seizure-onset zone, which can be large and widespread in the human brain (Tønnesen & Kokaia, 2017). The transduction volumes need to be addressed by multiple viral vector injections, while light outreach can be increased by red-shifted opsins currently emerging in the literature (Guru et al., 2015). Indeed, these challenges do require future research.
Concluding Remarks
Optogenetics has been instrumental in addressing fundamental questions on ictogenesis and epileptogenesis in animal models both in vitro and in vivo. Much novel information has been obtained by applying inhibitory and excitatory opsins to selective populations of neurons in the local and remote components of epileptic networks, revealing intimate interactions between individual groups of cells orchestrating hypersynchronization and desynchronization activity. In the future, development of novel classes of opsins with better regeneration capacity and long-lasting activation with light pulses may further benefit the field. Particularly valuable will be the red-shifted opsin family that is currently growing with new members to develop noninvasive or less invasive optogenetics in freely moving animals bearing fiber-free miniaturized LED devices that will eliminate the damage to the brain caused by fiber implantation. Whether this powerful technique will be applied to human epilepsy still remains to be seen, given the challenges related to this approach that need to be addressed as described above. There is a significant effort in this direction undertaken by leading groups in the field, which certainly strengthens the hope for future translational value of optogenetic applications in humans.
Acknowledgments
ML and MA were supported by the Canadian Institutes of Health Research (PJT153310, PJT166178, and MOP130328) and the Savoy Foundation. MK was supported by the Swedish Research Council (2017-00921).
Disclosure Statement
Authors have no conflicts of interest to disclose
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