Abstract

In seizure conditions, neuro-glio-vascular immune communications, blood–brain barrier (BBB) damage, and synaptic circuitry functional remodeling are dynamic processes that unfold over time and by brain region. These processes are associated with the generation and maintenance of epileptic networks. Accumulating evidence suggests that pericytes and microglial cells play critical roles in contributing to epileptogenic events, with a specific and renewed attention to pro- and anti-inflammatory equilibriums that strictly depend on the disease stage. Implications for pericytes include BBB dysfunction during and after seizures, while microglia is involved in cerebrovascular and neural network remodeling through altered surveillance, phagocytic, and inflammatory responses. These cellular modifications can span from the epileptogenic foci to seizure-propagating regions or networks. Understanding how pericyte and microglial cells interact with neuronal and cerebrovascular structures will facilitate the development of multitarget pharmacological strategies for epilepsy. Within this framework, the timing of pharmacological intervention could dictate therapeutic success, in the light of the varying and contrasting inflammatory and neurovascular trajectories that are cell-specific and unfold after a seizure or during epilepsy.

Introduction: Neuro-Glio-Vascular Regulatory Cells in Seizure Networks

Over the last decade, numerous studies introduced novel roles for pericytes and microglial cells in the development and maintenance of a healthy brain and the pathophysiology of neurological disorders, including epilepsy (Giannoni et al., 2018; Klement et al., 2018, 2019; Milesi et al., 2014; Cheng et al., 2018; Eyo et al., 2016, 2021; Eyo and Wu, 2019; Wyatt-Johnson and Brewster, 2020). Pericytes and microglia can work independently as well as together, both to ensure a tight homeostatic control within networks for proper neuronal communication and to safeguard blood-brain barrier (BBB) tightness and physiological functions at the neurovascular unit (NVU) (Obermeieret al., 2013). Briefly, the BBB consists of a network of brain capillaries with a monolayer endothelium sealed by tight junctions, interfacing and segregating the brain parenchyma from the peripheral blood. Exact communications between the endothelial cells and the adjacent pericyte, astrocyte end-feet, and microglial cells continuously control BBB properties and NVU functions (Figs. 29–1 and 29–2). In a healthy system, the BBB is mostly impermeable to blood-borne molecules, and it finely tunes the brain homeostasis through a bidirectional control of peripheral-brain gradients of cells, molecules, and ions for correct synaptic transmission (Sweeney et al., 2019; Ghosh et al., 2011; Janigro et al., 2020). Considerable evidence supports cerebrovascular damage as a pathophysiological player in experimental and clinical epilepsy (Gorter et al., 2015; Librizzi et al., 2018; Marchi et al., 2011, 2012; Noe and Marchi, 2019; Swissa et al., 2019). In the healthy brain, pericytes participate in capillary stability, angiogenesis, and tightness of the endothelium (Attwell et al., 2016; Giannoni et al., 2018; Obermeier et al., 2013; Rustenhoven et al., 2017; Sweeney et al., 2019), while microglial cells surveil the perivascular space (Giannoni et al., 2018; Klement et al., 2018, 2019) and, in turn, promote neuronal survival and maintain synaptic circuitry (Kierdorf and Prinz, 2017). Evidence from humans and experimental models of epilepsy suggests that pericytes and microglia regulate immune and inflammatory responses that may have beneficial and detrimental consequences in the pathology of acute seizures and chronic epilepsy (Klement et al., 2019; Arango-Lievano et al., 2018).

Figure 29–1.

The endothelial-pericyte-glia interface in health and seizure conditions. A. At the neurovascular unit, endothelial cells (pink), pericytes (or smooth muscle cells depending on vessel caliber) (blue), astrocytes (green), neighboring microglial cells (more...)

Figure 29–2.

Examples of glio-pericytes structures at the cerebrovasculature. A. Two-photon acquisition of cortical brain arteries and NG2DsRed mural cells. B. Distribution of GFAP astrocytes and NG2DsRED pericytes in the cortex. NG2DsRED pericytes processes outline (more...)

Both pericytes and microglia react to bursts of neuronal hyperexcitability that subsequently change their morphology and functions. During and following seizures, pericytes detach from their mural positioning at the BBB endothelium and undergo damage and proliferation (i.e., pericytosis), thereby allowing instability and permeability of the BBB to occur. At the same time, microglial cells rapidly activate in response to seizures and migrate toward parenchymal neurons or to the perivascular space where their time-dependent detrimental or healing roles are studied (Figs. 29–1 and 29–3). Here, we provide basic definitions of pericyte and microglial cells along with their recently described roles in the regulation of neuronal activity and the NVU through the modulation of immune, pro- and anti-inflammatory, responses (Rustenhoven et al., 2017). The implication of pericyte damage in seizure conditions integrates the notion of BBB dysfunction in promoting abnormal neuronal firing (Arango-Lievano et al., 2018; Garbelli et al., 2015; Giannoni et al., 2018; Klement et al., 2018, 2019; Librizzi et al., 2018; Marchi and Lerner-Natoli, 2013; Milesi et al., 2014). Alongside, contemporary studies have disclosed novel roles for microglia, including potential control of neuronal activity when seizures occur in otherwise healthy systems, and impaired or improper phagocytosis of synaptic structures and/or neurons, all of which may be guided by a myriad of immune molecules such as cytokines and complement proteins (reviewed in Eyo et al., 2016; Eyo and Wu, 2019; Wyatt-Johnson and Brewster, 2020). Important from a cellular mechanism standpoint, understanding the spatiotemporal trajectories of pericytes and microglia modifications, and their contribution to epileptogenic processes, could lead to the development of novel diagnostic or pharmacological strategies (Giannoni et al., 2018, 2020).

Figure 29–3.

Microglial-neuronal interactions in health and seizure conditions. A. Under physiological conditions, microglia (red) occupy nonoverlapping territories in the brain parenchyma where they interact with neurons (green). B. During acute seizures, microglial (more...)

What Is a Pericyte?

Pericytes are mural cells, presenting a distinctive rotund soma with slim and long ramifications lining the abluminal side of the BBB endothelium (Attwell et al., 2016; Sweeney et al., 2016; Figs. 29–1 and 29–2). These cells were first described in 1873 and were referred to as Rouget cells. Later on, their name was changed to pericytes to reflect their close association to the endothelial cells. Pericytes form a tight sleeve, embedded in basement membranes, that provides essential structural and molecular support to regulate BBB stability, (re)growth, and hemodynamics (Attwell et al., 2016; Sweeney et al., 2019).

A heterogeneous population of pericytes with varying morphologies and protein expression profiles has been reported (Attwell et al., 2016; Sweeney et al., 2019). Pericytes localize along and around the walls of capillaries which they can either completely ensheath (i.e., circumferential processes) or partially cover (i.e., mesh pericytes; see Attwell et al., 2016, for review; Fig. 29–1). The molecular and functional properties associated with morphological heterogeneity of capillary pericytes remain to be deciphered (Attwell et al., 2016). Pericytes can be identified using immunostaining with antibodies against the glycoprotein CD13 and the platelet-derived growth factor receptor beta (PDGFRβ) or with transgenic mice (i.e., NG2DsRed). At the molecular level, the dynamic and physiological interplay between pericytes and endothelial cells is mediated by molecules that include PDGFRβ, tumor growth factor-β (TGF-β), and Notch Receptor 3, among others (Fig. 29–1D). Signaling through PDGFRβ, a tyrosine kinase receptor, promotes cerebrovascular integrity. TGF-β secreted by endothelial cells and pericytes binds to the TGF-β receptor 2 (TGFβR2) to activate the downstream Smad signaling cascade. This TGF-β/Smad signaling cascade inhibits pericyte proliferation and migration, promotes pericyte differentiation and attachment, and triggers the expression of extracellular matrix proteins. Lastly, the activated Notch3 receptor cleaves its intracellular domain to promote pericyte survival and cooperates with TGF-β/TGFβR2 to augment BBB stability (see Sweeney et al., 2016, 2019, for a comprehensive review). The latter signaling is also implicated in perivascular astrocyte dysfunction and cell inflammatory phenotype (Ivens et al., 2007).

Because of their unique perivascular localization at the BBB, the contribution of pericytes to inflammation, from either brain or blood-borne origin, is emerging (Giannoni et al., 2018; Rustenhoven et al., 2017). Pericytes mediate blood leukocytes’ extravasation into the brain parenchyma, allowing for the bidirectional propagation of peripheral and brain pro-inflammatory events to occur (Rustenhoven et al., 2017). Importantly, during inflammatory states, pericytes express an array of cytokines, chemokines, adhesion molecules (ICAM, VCAM), reactive oxygen and nitrogen species (ROS/RNS), and metalloproteinases (MMP2-9), all of which are associated with mechanisms underlying epileptogenic processes (Rustenhoven et al., 2017; Marchi et al., 2014; Vezzani et al., 2011, 2015; Fig. 29–1D). Pericytes also express elements of damage-associated molecular patterns (DAMPS) and pathogen-associated molecular patterns (PAMPS) which enable the propagation of immune responses between the periphery and the brain. Their inflammatory machinery encompasses typical elements, including nuclear factor kappa light chain enhancer of activated B-cells (NF-κB), production of interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα), and the expression of major histocompatibility complex class II (MHCII) (see Rustenhoven et al., 2017, for review). In addition, pericytes have been shown to have phagocytic properties which may facilitate the uptake of damaged cells and waste products for interstitial clearance, to secrete mediators polarizing or activating microglia, and to internalize antigens for T-cell presentation (Rustenhoven et al., 2017).

Perivascular Inflammatory Cell Reactivity during Seizures: Focus on Pericytes

Pericyte damage, remodeling, and reactivity are implicated in the progression or severity of neurological diseases, including Alzheimer disease (AD), traumatic brain injury (TBI), ischemic stroke, and epilepsy (Giannoni et al., 2018; Sweeney et al., 2016, 2019). Here, we focus on the emerging roles of pericytes in experimental seizure conditions. Structural deconstruction and reactivity of pericytes and glial cells around the capillary endothelium (or perivascular) directly impact BBB permeability and it participates in neuroinflammation (Sweeney et al., 2019; Rustenhoven et al., 2017). Whether pericytes reactivity precedes or follows the occurrence of a seizure, BBB dysfunction, and increased permeability is unknown. Elucidation of these aspects will contribute to understanding pericyte involvement in the disease (Bar-Klein et al., 2017; Kastanauskaite et al., 2009; Marchi et al., 2007; Ivens et al., 2007; Pavlovsky et al., 2005; Seiffert et al., 2004). BBB damage can be prompted by pro-inflammatory factors such as IL-1β and IL-6 (Vezzani et al., 2011, 2019) and by local increases of extracellular glutamate concentrations (Vazana et al., 2016), which are events typically seen during seizure activity. A multicellular modification, or adaptation, occurs at the outer capillary wall after experimental status epilepticus (SE) and during seizure progression (Arango-Lievano et al., 2018; Giannoni et al., 2018; Klement et al., 2018, 2019; Milesi et al., 2014). By using NG2DsRed transgenic mice and FITC-Dextran micro-angiography, pericyte detachment from the BBB capillary in the dorsal hippocampus and overlying cortices was reported shortly after generalized SE induced by intra-peritoneal kainic acid (KA) injection (Milesi et al., 2014). Extending this initial evidence, during epileptogenesis and at spontaneous chronic seizures in a murine model of temporal lobe epilepsy (TLE, unilateral intra-hippocampal KA), NG2DsRed pericytes undergo a time-dependent detachment from the capillaries and a Ki67 ⁺ proliferation in the CA1 and CA3 hippocampal regions of the epileptic foci (Klement et al., 2018). During this process, pericytes lose their typical bump-on-a-log morphology, their minute perivascular ramifications, and they become hypertrophic (Klement et al., 2019; Librizzi et al., 2018; Boux et al., 2021). The latter resembled pericyte pathology (i.e., pericytosis) also reported after experimental traumatic brain injury (Zehendner et al., 2015). Precise and time-dependent dynamics of vessel-specific removal and addition of mural cells (smooth muscles and pericytes) were outlined using longitudinal 2-photon microscopy after a generalized SE in the somatosensory cortex (Arango-Lievano et al., 2018). Importantly, loss of pericytes negatively impacted cortical vasoreactivity in response to glutamate or endothelin-1 applications (Arango-Lievano et al., 2018). From a functional standpoint, the continuous remodeling of mural cells provoked by SE impacted in vivo vasoreactivity and blood flow (Arango-Lievano et al., 2018). Furthermore, BBB opening was preceded by capillary constriction with indications of pericyte injury-mediated loss of capillary integrity. Interestingly, reduced regional cerebrovascular reactivity was linked to mitochondrial depolarization in pericytes (Prager et al., 2019).

Importantly, pericytes were proposed to have immune-like properties and to participate in inflammatory responses, either peripheral or brain-borne (Smyth et al., 2018; Rustenhoven et al., 2017). This is important because overexpression of pro-inflammatory cytokines and chemokines occurs early in response to seizures, and players such as IL-1β can promote pericyte damage and microglia-pericyte assemblies at the cerebrovasculature (Klement et al., 2018). However, it remains to be understood whether these perivascular microglia-pericyte clusters are a component of restorative or detrimental processes.

What Are Microglial Cells?

Microglia are the tissue-specific macrophages and professional phagocytes of the central nervous system. These cells were first described by Spanish researcher Pío del Río Hortega in 1919. A century after, numerous scientific discoveries support that these cells are critically important for the development, maturation, and maintenance of neural circuitries (Prinz et al., 2019), and they contribute to the pathology of many neurological disorders (Hammond et al., 2018), including epilepsy (Wyatt-Johnson and Brewster, 2020; Eyo et al., 2016). Microglia are highly active cells that occupy and survey nonoverlapping territories throughout the brain (Fig. 29–3A), which in turn facilitates rapid responses to immune and homeostatic disturbances (Fig. 29–3B–D) (Eyo and Wu, 2019; Wyatt-Johnson and Brewster, 2020). These stimuli can trigger changes in microglial morphology from cells with highly ramified profiles to cells with hypertrophied and amoeboid shapes (Fig. 29–3D), which are associated with alterations in their functional status (i.e., surveillance, phagocytic, inflammatory).

The functions that microglia undertake under physiological and pathological conditions are tightly correlated to the expression of receptors specialized to sense and orchestrate appropriate responses to “find-me,” “eat-me,” and “don’t-eat-me” signals in their microenvironment (Sierra et al., 2013). Under physiological conditions, ramified microglia are constantly patrolling/surveying the brain by following ADT/ATP gradients (“find-me” signals) through purinergic receptors such as P2Y12 (Eyo and Wu, 2019). Phagocytic receptors, such as the triggering receptor expressed in myeloid cells 2 (Trem2), receptor Mer Tyrosine Kinase (MerTK), Vitronectin receptors (VNR), and complement receptors 1 and 3 (CR1, CR3), can promote the rearrangement of the cytoskeleton and help induce phagocytosis (Sierra et al., 2013; Brown and Neher, 2014; Konishi and Kiyama, 2018). Some “eat-me” signals that activate these receptors are lipids and DNA for Trem2, phosphatidylserine (PS) exposed on the surface of stressed or apoptotic cells bound to the opsonins Protein S (ProS) or Milk fat globule epidermal growth factor 8 (MFG-E8), which are ligands for MerTK and VNR, respectively, complement C1q for CR1, and complement C3b for CR3. These phagocytotic signals can be balanced by “don’t-eat-me” signals such as the integrin-associated protein CD47 that is sensed by the regulatory protein α (SIRP-α) receptor to inhibit phagocytosis. Receptors such as the colony-stimulating factor 1 receptor (CSF1R) are activated by the colony-stimulating factor 1 (CSF1) or interleukin 34 (IL-34) to regulate various functions involving inflammatory and phagocytic responses, as well as microglial survival and proliferation (Ulland et al., 2015; Oosterhof et al., 2018; Elmore et al., 2014). Activation of the complement system leads to downstream activation of C3a/b and C5a/b signaling that can regulate microglial phagocytic and inflammatory responses (Barnum, 2017; Schartz and Tenner, 2020), while Toll-like receptors (TLR) signal for the production of cytokines (van Vliet et al., 2018). Microglia can produce pro- and anti-inflammatory cytokines, including IL-1β and TNFα, which promote inflammation, and IL-4, IL-10, and IL-13, which help produce anti-inflammatory signals (Hiragi et al., 2018; Ravizza and Vezzani, 2018). Note that all these different signaling cascades can activate downstream pathways that can crosstalk with each other and thereby regulate or control the extent of both phagocytic and inflammatory responses (Sierra et al., 2013). New evidence over the last decade support that dysregulation of microglial surveillance, phagocytic, and inflammatory properties participate in the neuropathology and pathophysiology of epilepsy in humans and preclinical models. In this section, we summarize and discuss some of these findings.

Microglia Surveillance and Neuronal Interactions

Microglial cells are constantly surveying their microenvironment and making contacts with nearby neurons in an activity-dependent manner (Eyo and Wu, 2019; Eyo et al., 2016). This process is important for a rapid immune response and necessary for the proper development and maintenance of synaptic circuitries (Hammond et al., 2018). The glia-neuron interactions are mediated, in part, by microglial P2Y12R responses to microgradients of ATP (Eyo and Wu, 2019). Seizures promote an increase in the levels of ATP (Beamer et al., 2019), and along with this, microglial processes interact more frequently with neuronal elements (Hasegawa et al., 2007; Brewster et al., 2013; Eyo et al., 2014, 2015, 2016, 2017, 2021). Recent studies showed that seizure-induced increases in microglial-neuronal contacts were dependent on P2Y12R (Eyo et al., 2014), fractalkine signaling (CX3CL1-CX3CR1) that was coupled with increases in IL-1β (Eyo et al., 2017), neuronal NMDA receptor activation (Eyo et al., 2014), and extracellular calcium (Eyo et al., 2014, 2015). Interestingly, these studies also showed that mice deficient in P2Y12R or CX3CR1 displayed higher seizure severity following KA or pilocarpine-induced seizures (Eyo et al., 2014, 2016, 2017), suggesting that microglial surveillance functions are important to reduce neuronal hyperexcitability when a seizure is induced in an otherwise healthy system. This is further supported by a recent study showing that decreasing microglia ability to survey their microenvironment by inhibiting the Gi pathway, needed for the downstream activation of signaling pathways dependent on G protein–coupled receptors (GPCRs), results in unprovoked seizures and network hypersynchrony in mice (Merlini et al., 2021). This evidence suggests that microglial surveillance properties are altered in response to seizures and may work to dampen the sudden neuronal hyperexcitability that promotes more seizures. However, questions remain on how exactly microglia achieve this effect.

Microglia can shape the connectivity of synaptic networks in an activity- or experience-dependent manner (Schafer et al., 2012; Stevens et al., 2007; Prinz et al., 2019; Tay et al., 2017; Tremblay et al., 2010). The activity-driven increase in glial-neuronal contacts may result in modifications to synaptic structures because microglia have been shown to displace, eliminate, or promote the growth of synaptic elements (Tremblay et al., 2010; Weinhard et al., 2018; Miyamoto et al., 2016; Wake et al., 2009; Wan et al., 2020; Chen et al., 2014; Hammond et al., 2018). For example, microglial-mediated displacement of GABAergic synapses has been shown to occur in developing brains exposed to complex febrile seizures (FS) (Wan et al., 2020) and in adult brains subjected to lipopolysaccharide (LPS)-induced microglial activation (Chen et al., 2014). Following FS induced in young mice, an increased association of microglial processes with the soma of cortical neurons was coupled to an absence in GABAergic terminals, reduced GABAergic postsynaptic currents, and decreased frequency of evoked action potentials compared to neurons with less or without microglial associations (Wan et al., 2020). These effects were abolished with pharmacogenetic-induced reductions of P2Y12R, thereby suggesting that seizure-induced P2Y12R-dependent microglial-neuronal contacts are neuroprotective in the immature brain. Similarly, LPS-induced microglial activation in adult mice or rats resulted in increased microglial enwrapping of the soma of cortical neurons, reduced GABAergic neurotransmission, and increased synchronized neuronal firing (Chen et al., 2014). Even though activation of microglia had a similar effect in enwrapping and displacing GABAergic synapses in the immature and adult brain, the impact on network hyperexcitability was the opposite, likely due to the excitatory role for GABA early in life (Ben-Ari et al., 2012). The activated microglial-mediated displacement of GABAergic synapses in an adult system may potentiate the neuronal hyperactivity that results in seizures, suggesting age-specific roles for microglia in the pathogenic sequelae of prolonged seizures.

Complement proteins such as C1q and C3 act as guides in microglia-mediated synaptic stripping during normal development and in neurodegenerative disorders (Schafer et al., 2012, 2013; Stephan et al., 2012; Stevens et al., 2007; Carpanini et al., 2019; Prinz et al., 2019). In the normal developing retinogeniculate system, C1q and C3b promote the elimination of weak or uncoupled synaptic elements suggesting that the complement pathway contributes to the stability of the newly formed circuits (Schafer et al., 2012, 2013; Stephan et al., 2012; Stevens et al., 2007). Complement C3 is upregulated in aging, neurodegenerative disorders (Carpanini et al., 2019; Prinz et al., 2019), and epilepsy (Wyatt-Johnson and Brewster, 2020), suggesting that complement-mediated synapse elimination may be a mechanism associated with the microglia-neuronal contact-mediated regulation of neuronal activity discussed above. Clinical studies revealed higher levels of circulating C3 (Başaran et al., 1994), terminal complement proteins, and Factor H (Kopczynska et al., 2018), as well as increases in C1q and C3 mRNA and C3b protein levels in the brain (Aronica et al., 2007; Wyatt-Johnson and Brewster, 2020; Wyatt et al., 2017). In preclinical models, complement mRNA and proteins are upregulated in the brain both acutely after prolonged seizures and in the chronic epilepsy stage (Aronica et al., 2007; Schartz et al., 2016, 2018). In epileptic rats, increased C3 levels are significantly correlated with the frequency of spontaneous seizures and parallel deficits in hippocampal-dependent memory deficits (Kharatishvili et al., 2014; Schartz et al., 2018, 2019). In addition, significant correlations between increased levels of C3 protein and decreased levels of the synaptic markers PSD95, VGlut, and VGat were found in hippocampi of rats subjected to SE (Schartz et al., 2019). Studies done blocking downstream complement components such as C3 and C5 (and their receptors) reduced seizure frequency or severity (Libbey et al., 2010; Buckingham et al., 2014; Benson et al., 2015b), though suppressing C1q signaling upstream of C3 did not improve memory defects induced by SE (Schartz et al., 2019), and C1q KO mice developed epilepsy (DeVos et al., 2013; Chu et al., 2010). Taken together, this evidence suggests that microglia-neuronal contacts that occur following acute seizures or in chronic epilepsy may result in synaptic remodeling. Potential protective or detrimental outcomes would depend on the type of synapse targeted, brain region affected, and age (Andoh et al., 2019). Further investigation is required to fully understand how microglia-neuronal interactions modulate the epileptic brain and what immune molecules may be underlying the changes in synaptic activity.

Microglial Pro- and Anti-inflammatory Molecular Equilibriums in Experimental Epilepsy

Microglia with reactive properties are widely found in models of genetic and acquired epilepsies (Wyatt-Johnson and Brewster, 2020; Brewster, 2019; Eyo et al., 2016; Sabilallah et al., 2016). It is well established that microglia develop an inflammatory phenotype during and after seizures (van Vliet et al., 2018; Devinsky et al., 2013), and more recent studies support that this is coupled with dysfunction in microglial phagocytic activity (Abiega et al., 2016; Zhao et al., 2018; Sierra-Torre et al., 2020; Luo et al., 2016; Koizumi et al., 2007). In a rat model of acquired epilepsy triggered by pilocarpine-induced SE, drastic alterations in microglial morphologies and densities in the hippocampus that varied in a spatiotemporal-dependent manner were found during the period of epileptogenesis between 4 h and 5 weeks after SE (Wyatt-Johnson et al., 2017; Schartz et al., 2016). Early after SE (4 h), microglia developed a hypertrophied morphology that paralleled significant increases in the levels of TNFα and IL-6 measured in hippocampal homogenates. However, at 2 weeks post-SE, when microgliosis peaked in the hippocampus, or at 5 weeks when the animals reached chronic epilepsy, no significant changes were found in at least 24 different cytokines (Schartz et al., 2016), suggesting that the functions of microglia evolve during epileptogenesis. In agreement with these findings, studies reported increases in the pro-inflammatory cytokines IL-1β, TNFα, IL-6, and IL-12, as well as the anti-inflammatory molecules Arg1, Ym1, IL-10, and IL-4 in isolated microglia at 3 days after pilocarpine-induced seizures, all not modified in the chronic epilepsy phase (Benson et al., 2015a). In comparative analyses using the KA model of mesial (m)TLE, the pro-inflammatory cytokines at 3 days after SE did not last into the chronic phase (Benson et al., 2015a). The presence of reactive microglia with inflammatory signatures has been extensively reported in different types of epilepsies (see van Vliet et al., 2018), including TLE (Broekaart et al., 2018; Schartz et al., 2016, 2019), focal cortical dysplasia (FCD) (Nguyen et al., 2015), tuberous sclerosis complex (TSC) (Nguyen et al., 2019; Zhang et al., 2018; Zimmer et al., 2020), models of encephalitis (Pitsch et al., 2021; Bell et al., 2020), and developmental seizures (Patterson et al., 2015). While causal mechanisms underlying microglial inflammatory responses are not definitively known, existing evidence suggests that enhanced neuronal firing, accompanied by excitotoxicity, neuronal loss, and interplays of peripheral immune cells (i.e., CD8 ⁺ T-cells and monocytes) at the neurovascular unit can trigger the activation of microglial cells (Pitsch et al., 2021; Varvel et al., 2016). This microglia-mediated inflammation may have beneficial (i.e., tissue repair, neuroprotection) or detrimental (i.e., neurodegeneration) consequences to the surrounding neural networks depending on whether inflammation is short- or long-lasting (DiSabato et al., 2016) and the brain regions affected (i.e., epileptogenic foci and seizure-propagating).

In parallel to inflammatory changes, several studies demonstrated alterations in microglia phagocytic activity that may be pro-epileptogenic in genetic and acquired models of epilepsy (see Wyatt-Johnson and Brewster, 2020, for review). A recent study showed that deletion of the TSC1 gene specifically in microglial cells (TSC1^CX3CR1CKO) caused enhanced activation of the mechanistic target of rapamycin (mTOR) in microglial cells and recurrent unprovoked seizures (Zhao et al., 2018). The microglial population in the TSC1^CX3CR1CKO mice displayed amoeboid and bushy morphologies, decreased levels of IL-1β, IL-6, TNFα, and iNOS, among other inflammatory molecules, and increased phagocytic activity (Zhao et al., 2018), thereby suggesting that noninflammatory phagocytic microglia may underlie epilepsy in this TSC model. This study also showed that microglial mTOR signaling is necessary for proper microglial phagocytic functions as mTOR-deficient microglia showed a phagocytosis impairment, and the microglial mTOR-deficient mice developed severe spontaneous seizures (Zhao et al., 2020). Thus, it is possible that disrupting the fine balance of inflammatory/phagocytic properties of microglia can result in hyperactive neuronal networks. However, it is noted that a different study utilizing similar TSC1^CX3CR1-CreCKO mice showed that enhanced mTOR signaling increased microglial cell size, although spontaneous seizures did not develop (Zhang et al., 2018; Wong, 2019). Yet a recent study interrogating epigenetic regulation of microglial clearance activity showed that mice lacking the polycomb repressive complex 2 (PRC2) molecule, which controls the expression of microglial-specific clearance genes, developed epilepsy (Ayata et al., 2018). This evidence further suggests that increased microglial phagocytosis activity may contribute to the generation of spontaneous recurrent seizures.

Abnormal microglia-mediated phagocytosis and its role in epileptogenesis and chronic epilepsy were also reported in animal models of acquired epilepsy (Wyatt-Johnson and Brewster, 2020). Following KA-induced seizures in the rat, microglial phagocytic activity was increased in the hippocampal CA3 region, and this was mediated by UDP/P2Y6-dependent signaling (Koizumi et al., 2007). In contrast, a microglial phagocytic deficiency was found in the hippocampal dentate gyrus (DG) following intrahippocampal administration of KA in mice. In this study, the molecular signatures of fluorescence-activated cell sorting (FACS)-isolated microglia included decreased mRNA levels of the phagocytosis receptors Trem2, MerTK, CR3, and GPR34, and increased levels of the purinergic receptors P2Y12, P2Y6, and P2X4, along with cytokines such as IL-1β, IL-6, and TNFα (Abiega et al., 2016). These molecular changes occurred in association with a decrease in both microglial phagocytic activity and surveillance/motility within the DG area. As a result, newborn apoptotic cells were not phagocytosed and accumulated, possibly potentiating detrimental and pro-epileptogenic inflammatory responses (Abiega et al., 2016). A microglial phagocytosis impairment in the hippocampal DG was also observed in a mouse model of progressive myoclonus epilepsy type 1 (Sierra-Torre et al., 2020). The differences in microglial phagocytic responses in the hippocampal CA3 versus DG areas are likely due to the extent of regional vulnerability to neuronal death, which can trigger increases in microglial P2Y6 receptors, thereby enhancing phagocytic activity of these cells (Koizumi et al., 2007). Interestingly, it has also been shown that microglial cells can engulf and phagocytose “healthy” nonapoptotic cells in the hippocampal DG area during epileptogenesis (Abiega et al., 2016; Luo et al., 2016). This process is known as phagoptosis (Brown and Neher, 2014) and may contribute to exacerbated neuronal loss in epilepsy. These observations suggest that seizures per se can cause long-lasting disruptions in the microglial phagocytic activity that are region-dependent. These findings, along with evidence from human drug-resistant epilepsies, support that dysregulation of the equilibrium of microglial phagocytic and inflammatory functions may be epileptogenic.

Microglia-Pericytes Perivascular Assembly and Reactivity during Seizures: Experimental and Clinical Evidence

The reported redistribution of mural cells (smooth muscle cells and pericyte) at the perivascular compartment is intertwined with dynamic and time-dependent modifications of astrocytes and microglial cells. Evidence exists for CNS diseases, in particular for experimental autoimmune encephalopathy (EAE) (Merlini et al., 2019; Davalos et al., 2012) or AD (Ryu and McLarnon, 2009; Halder and Milner, 2019), where the perivascular accumulation of microglial cells topographically overlapped with blood fibrinogen entry into the brain parenchyma, promoting neuronal and dendritic spine damage or elimination. In an experimental TLE model, GFAP-labeled astrocytes, IBA1-positive microglia, and NG2DsRed pericytes spatially converge to form a complex, multicellular and dynamic assembly at the outer wall of the BBB (Garbelli et al., 2015; Giannoni et al., 2018; Klement et al., 2018). In the hippocampal epileptic foci (ih KA), activated microglial cells accrue the outer BBB wall, possibly exerting a phagocytic action towards damaged pericytes (Fig. 29–1; Klement et al., 2018).

In these regions, increased PDGFRβ expression indicated a fibrotic-like mesh developing around the capillaries (Klement et al., 2019). Partaking in this multicellular perivascular reorganization, abnormal collagen deposits could confer stiffness to specific vascular portions, and exacerbate neuroinflammation (Klement et al., 2019). Evidence of collagen accumulation also derives from human TLE (Klement et al., 2019; Kastanauskaite et al., 2009). These data suggest the presence of fibrotic elements, indicating a possible perivascular scar at sites of BBB leakages, the latter identified by using intravenous fluorescein during epileptogenesis and at spontaneous seizures (Klement et al., 2019). Furthermore, a pathological matrix MMPs production was reported during epileptogenesis, and the use of an MMP2/9 inhibitor (IPR-179) reduced seizures in experimental models, also curbing seizure-associated cognitive defects (Broekaart et al., 2021). Further indicating the presence of pro-fibrotic events is an increase of parenchymal PDGFRβ reactivity during seizures in the hippocampal epileptic focus (Dias et al., 2018). The exact origin of PDGFRβ cells during disease conditions is debated, possibly originating from the activated or damaged pericytes detaching from the vascular wall (Dias et al., 2018; Goritz et al., 2011; Cheng et al., 2018) or, otherwise, proliferating from an existing pool of fibroblasts (Soderblom et al., 2013; Riew et al., 2018). In any case, this perivascular multicellular activation could promote localized rigid scars, with negative implications to the control of vascular tone (Arango-Lievano et al., 2018) and the regulation of neurovascular coupling during seizures (Prager et al., 2019b). The presence of perivascular microglial cells and pericyte damage was also reported in human TLE and FCD type IIb brain tissues (Garbelli et al., 2015; Klement et al., 2018; Milesi et al., 2014). In TLE with neuronal loss and gliosis in the hippocampus (hippocampal sclerosis; HS), microglial cells (IBA1 and activated HLA) were found around the capillaries, as compared to nonlesional TLE (Klement et al., 2018). Alongside, PDGFRβ⁺ immunoreactivity was evident at the capillary level in TLE-HS. In FCD IIb brain specimens, perivascular pericytes and microglia (IBA1, HLA) were reported in the core of the dysplastic regions, as compared to the adjacent normal-appearing areas (Garbelli et al., 2015; Klement et al., 2018).

Less obvious is whether pathological glio-vascular variations exist in seizure networks and in the absence of a clear-cut inflammatory phenotype or tissue lesion. The latter notion is relevant as varying physiological neuronal activities can finely tune glio-vascular gene expression patterns (Pulido et al., 2020), while nonlesional seizure-propagating brain regions can display distinct imaging signatures (Boux et al., 2021). Remodeling of capillary pericytes was shown to occur in the seizure propagating hippocampi of a TLE mouse model, in areas characterized by the absence of tissue sclerosis or apparent histological signs of inflammation (Boux et al., 2021). An increase in the MRI parameters apparent diffusion coefficient, blood volume fraction, and BBB permeability occurring in the contralateral hippocampus (of the unilateral ih KA model) correlated with an augmented CD13 pericytes length, an indication of cell hypertrophy or a previous angiogenesis (Boux et al., 2021). Taken together, these data indicate the presence of discrete pathological signatures generated by seizure propagation routes, independent from the existence of histological, tissue-level, lesions.

Microglial Profiles in Human Drug-Resistant Epilepsies

The heterogeneity of microglial morphological and immune signatures is evident in brain tissues surgically resected from patients with drug-resistant epilepsies, including FCD, TSC, Rasmussen encephalitis (RE), and mTLE-HS. Histological analyses of these tissues support a microglial pathology in epilepsy that is first seen through morphological alterations. For example, microglia with hypertrophied and amoeboid shapes are present in cortices and hippocampi of FCD, RE, TSC, and mTLE patients, suggesting a reactive phenotype (Wyatt et al., 2017; Wirenfeldt et al., 2009; Boer et al., 2008a, 2008b; Broekaart et al., 2018; Xu et al., 2018; Altmann et al., 2021). Microglia with these “reactive” shapes are more abundant in areas closer to the seizure focus as well as within microlesions characterized by high spiking activity (Dachet et al., 2015; Morin-Brureau et al., 2018). In human mTLE, amoeboid microglia were found in hippocampal areas CA1 and CA3 associated with high neuronal death when compared to the DG or subiculum where the neuronal loss was less prominent (Morin-Brureau et al., 2018). In addition, a recent study utilizing a systems-level analysis of image-based cortical structural profiles along with gene expression data from human epilepsy cases also showed a high density of microglial cells in areas characterized by reduced cortical thickness (Altmann et al., 2021). Even though the presence of reactive microglia in human epileptic brains correlates with areas of decreased neuronal densities and increased vascularity (Dachet et al., 2015; Morin-Brureau et al., 2018; Altmann et al., 2021), and microglia have been found in close association with injured dendrites (Wyatt et al., 2017; Wirenfeldt et al., 2009), dysmorphic neurons, cortical tubers (Boer et al., 2008a, 2008b), and apoptotic cells (Abiega et al., 2016), their role in the pathology of epilepsy is not definitively known.

To understand exactly how microglia may contribute to hyperexcitable circuits, it is necessary to obtain information on their molecular profiles. In human epileptic tissues, immunohistological studies showed that amoeboid microglia were abundant in MHCII, phagocytic-associated molecules CD68 and CD16/32a (Morin-Brureau et al., 2018), complement proteins (Aronica et al., 2007; Wyatt et al., 2017), and inflammatory molecules (Morin-Brureau et al., 2018; Hiragi et al., 2018; van Vliet et al., 2018), suggesting a reactive phenotype. In mTLE, both amoeboid and ramified microglia expressed the purinergic receptor P2Y12 and retracted their processes similarly in response to ADP exposure in culture (Morin-Brureau et al., 2018). This interesting finding contrasts the ADP/ATP-triggered extension of microglial processes seen under physiological conditions in preclinical models (Eyo and Wu, 2019). Furthermore, transcriptome analyses from whole-tissue biopsy homogenates showed differentially expressed microglial-specific genes that support altered microglial-related molecular signatures in areas of high and low spiking activity or neuronal death (Dachet et al., 2015; Morin-Brureau et al., 2018). High expression of markers for microglial M1 and M2 polarization (with higher M1/M2 ratio) (Dachet et al., 2015) and upregulations in levels of cytokines such as IL-10, IL-1β, CXCL8, CXCR4, and CCR5 were found in the epileptic tissues (Morin-Brureau et al., 2018). Other changes of microglial-related proteins recently described in drug-resistant epilepsies include increases in C1q, C3b, and MerTK (Wyatt et al., 2017) and decreases in Protein S, Trem2, CD47, and SIRP-α (Wyatt et al., 2017; Sun et al., 2016).

To specifically study microglia in surgically resected samples (biopsies) from epileptic patients, recent studies utilized high-throughput techniques based on combinations of single-cell RNA sequencing (scRNA-seq), multiplexed single-cell mass cytometry (CyTOF), FACS, and bioinformatics. The results support that the biological profiles of microglia vary in a spatial- and age-dependent manner in the human brain (Gosselin et al., 2017; Galatro et al., 2017; Sankowski et al., 2019; Masuda et al., 2019; Bottcher et al., 2019; Brewster, 2019). These studies used perilesional tissues from epilepsy surgeries along with human brain autopsy samples, among others, and while not specifically investigating the pathology of epilepsy, their findings can help elucidate specific microglial functions that are particularly relevant to the human epileptic brain. RNA-seq of FACS-isolated microglial cells demonstrated a robust expression of P2Y12, Trem2, and the CX3C chemokine receptor 1 (CX3CR1) along with the complement proteins C3 and C1q in these cells (Gosselin et al., 2017). Microglial cells extracted from epilepsy cases and processed through CyTOF showed a robust expression of the MHCII surface receptor human leukocyte antigen-DR isotype (HLA-DR), Trem2, P2Y12, interferon regulatory factor 8 (IRF8), and CD68 (Bottcher et al., 2019). In parallel, this study showed diverse microglial immune signatures across five different brain regions, with areas such as the subventricular zone containing microglia rich in CD68 along with the cyclins A and B1, and the nuclear protein Ki-67, which participate in cell growth and proliferation (Bottcher et al., 2019). Other regional changes include higher expression of CD68 and HLA-DR in microglia localized to the white matter compared to those in the grey matter (Sankowski et al., 2019). Comparative analyses of microglial immune profiles between human epilepsy biopsies and mice showed higher biological heterogeneity with more activated phenotypes in humans (Masuda et al., 2019), which could be related to not only intrinsic species differences but also to a history of drug-resistant seizures. Taken together these data support that microglial cells in the human epileptic brain have diverse biological features which may result in altered surveillance, inflammatory, and phagocytic roles that vary by brain region, as well as by the extent of neuronal density and seizure activity.

Additional evidence supporting a role for microglia in epilepsy comes from a study describing two cases in which homozygous mutations in the CSF1R gene, a signaling molecule that regulates microglial survival (Elmore et al., 2014), caused brain malformations, leukoencepatholpathy, and epilepsy (Oosterhof et al., 2019). Loss-of-function mutations in CSF1R are typically associated with reduced numbers of microglia in individuals diagnosed with adult-onset leukoencepatholpathy with axonal spheroids and pigmented glia (ALSP), which develop epilepsy in adulthood (Oosterhof et al., 2019). A study describes two pediatric cases in which CSFR1 mutations were associated with both the development of intractable epilepsy in an 8-month-old infant that died prematurely at 10 months, and with childhood epilepsy and developmental regression that occurred at age 12 years in the second individual. Interestingly, histological analysis showed a lack of microglial cells in the brain of the infant, suggesting that microglia are critically important for postnatal brain development and to modulate/control neural activity. These findings in human are also supported by pharmacogenetic manipulations of CSF1R signaling in preclinical models (discussed below).

Pharmacological Entry Points: Focus on Pericytes and Microglia

To study how microglia may contribute to the neuropathology and the pathophysiology of epilepsy, recent studies focused on pharmacogenetic manipulations of the CSF1R signaling cascade. CSF1R is mainly found in microglia and functions to control the survival of these cells (Ulland et al., 2015; Oosterhof et al., 2018; Elmore et al., 2014; Waisman et al., 2015). A systems-level framework analysis for target drug discovery using mRNA samples extracted from hippocampi of pilocarpine-treated mice identified CSF1R as a potential target for epilepsy treatment (Srivastava et al., 2018). In this study, CSF1R signaling was suppressed with the drug Plexxikon (PLX) 3397, which was administered for 2 weeks to chronically epileptic mice. PLX3397 caused a significant decrease in the microglial population in both hippocampus and cortex, and a reduction in seizure frequency and duration (Srivastava et al., 2018), suggesting that microglia contribute to the maintenance of an epileptic brain. In contrast, other studies have shown that depletion of microglia can worsen the seizure pathology. For example, microglial suppression starting at least 3 weeks after SE aggravated the seizure severity in chronically epileptic mice (Wu et al., 2020), and microglial depletion before the administration of chemoconvulsants/stimulants (KA, picrotoxin, or D1 agonist) or a Theiler’s murine encephalomyelitis virus resulted in more severe seizures (Wu et al., 2020; Badimon et al., 2020; Sanchez et al., 2019). Recent studies support that the timing of microglial suppression can impact the outcome of seizure burden and associated cognitive comorbidities in rodent models of SE and acquired TLE (Altmann et al., 2021; Di Nunzio et al., 2021; Wyatt-Johnson et al., 2021). PLX3397 treatment given immediately after SE and for 3 consecutive weeks during the period of epileptogenesis significantly decreased hippocampal microgliosis without altering hippocampal-dependent spatial learning and memory defects in rats (Wyatt-Johnson et al., 2021). Similarly, others showed that treatment with the CSF1R suppressor GW2580 during SE-induced epileptogenesis did not alter either the seizure or memory pathology (Di Nunzio et al., 2021). However, when GW2580 was given to mice with fully established epilepsy, seizure severity decreased and cognitive performance improved, suggesting that microglia may have different functions in developing and established epileptic networks (Di Nunzio et al., 2021). However, existing studies do not account for the heterogeneous populations of microglia that exist throughout the brain, with different molecular signatures and biological functions that may serve beneficial or detrimental effects in the epileptic brain. Therefore, additional research is required to differentiate the impact that alterations in different microglial functions (surveillance, inflammatory, and phagocytic) have on epilepsy pathophysiology. Once these are identified, more efficacious treatments that specifically target the detrimental signaling can be developed.

When studying the functional impact of pericytes in seizure conditions, PDGFRβ was targeted to modify the pathological neurovascular sequelae of SE in vivo or during epileptiform conditions in vitro (Klement et al., 2019; Arango-Lievano et al., 2018). A restorative or a protective effect was reported when the PDGFRβ agonist ligand PDGF-BB was administered early post-SE in mice (Arango-Lievano et al., 2018). However, during epileptogenesis leading to spontaneous seizures, the PDGFRβ increase was associated with a scarring process, advocating for the use of a receptor blocker, such as imatinib, to curb inflammation (Klement et al., 2019). From this evidence we understand that the outcome of PDGFRβ modulation may be contingent on the disease stage, that is, early post brain insults (SE, head trauma, ischemic stroke) pericytes necessitate support via PDGFRβ activation, whereas a pro-inflammatory involvement of PDGFRβ may emerge during chronic stages, perhaps necessitating inhibition. Because of the rapidly evolving pro- and anti-inflammatory equilibriums and dynamics during epileptogenesis, targeting a specific player may be oversimplistic, considering the multiple roles that neuro-glio-vascular cells have as a function of time and region.

Conclusion: Refining Timing and Targets for Pharmacological Interventions

Experimental and clinical epilepsies can be considered neuro-glio-vascular pathological conditions. This notion is important because the next antiseizure solutions could include the combination of neuronal and glio-vascular molecules, targeting multiple and interindependent culprits of seizures. Adding a level of complexity, time for pharmacological intervention needs to be carefully planned, because of the varying, even contrasting, functions that a specific cell type can acquire during disease progression. Based on contemporary evidence, we identify several research opportunities and questions: (1) what are the temporal dynamics governing the pericyte and microglial mediated anti- and pro-inflammatory cellular (dys) equilibrium unfolding during seizure progression? Recent evidence identified insufficient engagement of endogenous anti-inflammatory pathways (i.e., glucocorticoid receptors/annexin A1, n-3 docosapentaenoic acid) during experimental seizures, enabling inflammation (Frigerio et al., 2018; Zub et al., 2019). Promoting resolution of inflammation by boosting endogenous mechanisms could represent a new therapeutic frontier (Fullerton and Gilroy, 2016); (2) what are the roles of microglia activation and differential redistribution toward the capillaries and neurons? Recent evidence demonstrated that microglial cells can accumulate at the perivascular compartment in response to seizures, in models of autoimmune encephalitis, and AD (Bauer et al., 2008; Davalos et al., 2012; Giannoni et al., 2018; Halder and Milner, 2019; Klement et al., 2018, 2019; Merlini et al., 2019; Ryu and McLarnon, 2009), overlapping with regions of BBB permeability, as well as in areas of high neuronal spiking and cell death. At the same time, neuronal hyperexcitability and seizures trigger increases in the physical interactions between microglial processes and different neuronal structures (i.e., soma, dendrites), whose exact roles, pro- or anti-epileptogenic, are yet to be determined. Similarly, whether alterations in levels of phagocytosis-related molecules and microglial phagocytic actions (enhanced or impaired) as well as if the associated release of pro- or anti-inflammatory molecules are a cause or a result of seizures is not known. To determine how pericytes and microglial cells contribute to epilepsy, future studies must perform comprehensive spatiotemporal mapping of biological profiles of these cell types as well as the interactions with neurons and blood vessels both during and after acute seizures and in the chronic epilepsy stage. Based on recent evidence described throughout this review, populations of pericytes and microglia with different profiles that may be beneficial or detrimental can coexist in the epileptic brain. This suggests that time-targeted, regional, and cell-specific interventions may represent a strategy that can reduce the harmful signals or enhance the beneficial actions of antiepileptic drugs (Ghosh et al., 2011).

Acknowledgments

Disclosure Statement

References

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