Seizures in Mouse Models of Rare Neurodevelopmental Disorders

Journal Pre-proofs Review Seizures in Mouse Models of Rare Neurodevelopmental Disorders Merrick S. Fallah, James H. Eubanks PII: DOI: Reference:

S0306-4522(20)30071-3 https://doi.org/10.1016/j.neuroscience.2020.01.041 NSC 19500

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Please cite this article as: M.S. Fallah, J.H. Eubanks, Seizures in Mouse Models of Rare Neurodevelopmental Disorders, Neuroscience (2020), doi: https://doi.org/10.1016/j.neuroscience.2020.01.041

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Seizures in Mouse Models of Rare Neurodevelopmental Disorders Merrick S. Fallah 1,2 and James H. Eubanks 1,2,3,4 1

Division of Experimental and Translational Neuroscience Krembil Research Institute University Health Network 399 Bathurst Street Toronto, Ontario, M5T 0S8 Canada 2

Department of Pharmacology and Toxicology 3 Department of Physiology 4 Department of Surgery (Neurosurgery) University of Toronto Toronto, Ontario M5S 1A8 Canada

Corresponding Author: Dr. James Eubanks, Room 7-KDT-412, Krembil Research Institute, 60 Leonard Ave, Toronto, Ontario, M5T 0S8, Canada Telephone: (416) 603-5800 ext. 2933 E-mail: [email protected]

Word Count:

Abstract: 180 Manuscript Body: 7,468 References: 105 Tables: 0 Figures: 9

Keywords: Neurodevelopmental Disorders, Epileptic Encephalopathies, Seizures, Electroencephalography, Mouse Models

Running Title: Seizures in Neurodevelopmental Disorder Models

Abstract Genetic neurodevelopmental disorders that often include epilepsy as part of their phenotype are a heterogeneous and clinically challenging spectrum of disorders in children. Although seizures often contribute significantly to morbidity in these affected populations, the mechanisms of epileptogenesis in these conditions remain poorly understood. Different model systems have been developed to aid unraveling these mechanisms, which include a number of specific mutant mouse lines which genocopy specific general types of mutations present in patients. These mouse models have not only allowed assessments of behavioral and electrographic seizure phenotypes to be ascertained, but also have allowed effects on the neurodevelopmental alterations and cognitive impairments associated with these disorders to be examined. In addition, these models play a role in advancing our understanding of these epileptic processes and developing preclinical therapeutics. The concordance of seizure phenotypes - in a select

group

of

rare,

genetic,

neurodevelopmental

disorders

and

epileptic

encephalopathies - found between human patients and their model counterparts will be summarized. This review aims to assess whether models of Rett syndrome, CDKL5 deficiency disorder, Fragile-X syndrome, Dravet syndrome, and Ohtahara syndrome phenocopy the seizures seen in human patients.

Introduction Neurodevelopmental disorders are characterized by deficits in personal, academic, social, or occupational functioning (American Psychiatric Association, 2015, p. 5). These disorders in general are not considered uncommon as a whole, but the collective group houses several rare monogenetic conditions; many of them being diagnosed at early childhood stages. Although cognitive and motor impairments are common to many of these conditions, seizures or epilepsy syndromes are often an observed co-morbidity that can significant affect the patient’s quality of life. Seizures can be a debilitating aspect of neurodevelopmental disorders and are common to many conditions. Rare, monogenetic, neurodevelopmental disorders in which seizures constitute a major co-morbidity include Rett syndrome (Glaze, 2005; Tarquinio et al., 2017), Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (Fehr et al., 2016), Fragile-X syndrome (Kidd et al., 2014), and different forms of both Dravet syndrome (Archer et al., 2006; Berry-Kravis, 2002; Evans et al., 2005) and Ohtahara syndrome (Beal et al., 2012). Patients with any of these rare conditions often do not display a single or even common types of seizures, however, but rather can display a multitude of different seizure types that include focal, multi-focal, or generalized seizures (Crino et al., 2002; Glaze et al., 1998; Kato et al., 2007; S. A. Musumeci et al., 1999). In many cases, individual patients can display multiple different seizure types. Several models of rare monogenetic neurodevelopmental disorders currently exist, which include Rett syndrome (RTT) caused by MECP2 mutations, CDKL5 deficiency disorder (CDD), Fragile-X syndrome (FXS), Dravet syndrome, and Ohtahara

syndrome (OS). This review will summarize the clinical epilepsy features common to each condition, the phenotypes identified in their respective mouse models, and then discuss whether or not the mouse models recapitulate with good face validity the epileptic features observed in patients.

Rett Syndrome Clinical Presentation RTT, first described by Andreas Rett in 1966 (Rett, 1966), is most commonly caused by mutations within the methyl CpG binding protein 2 (MECP2) gene (Amir et al., 1999; Meehan et al., 1992). It is an X-linked neurodevelopmental disorder that affects mostly female patients (Kerr & Engerström, 2001). RTT is one of the most common monogenetic causes of severe neurodevelopmental impairments in girls, with an incidence of approximately 1 in 10,000 female births (Laurvick et al., 2006; Buchanan et al., 2019). Females with RTT are typically born asymptomatic, and many will meet several normal developmental milestones during the first year of life before symptoms and developmental regression appear (Hagberg et al., 1983; Kerr and Engerstrom, 2005; Chahrour and Zoghbi, 2007). RTT patients can display a spectrum of different impairments, with deficits in cognition, gastrointestinal mobility and reflux, ambulation and balance, and respiratory rhythm common to most patients (Hagberg et al., 1983; Kerr & Engerstrom, 2005). In addition to these, seizures are common, and can greatly affect the patient’s quality of life (Bahi-Buisson et al., 2008; Byiers et al., 2014). RTT patients are also at increased risk of sudden unexpected death, and in some cases this may be seizure-related (Byard, 2006).

Seizures in RTT patients are very heterogenous, with a wide spectrum of focal, multi-focal, and generalized seizure types commonly observed. These include focal impaired awareness (FIAS, previously known as complex partial), myoclonic, tonic, tonic-clonic and rarely absence epilepsies (Steffenburg et al., 2001; Huppke et al., 2007; Tarquinio et al., 2017). A study of epilepsy phenotypes in the Rett natural history study cohort reported generalized onset seizures in 47% of RTT patients, focal onset seizures in 46.8%, atonic seizures in 3.3% and myoclonic seizures in 1.7% (Tarquinio et al., 2017). Seizure onset is typically seen in early childhood but can arise infrequently in young adult patients (Huppke et al., 2007). Approximately 30-50% of RTT patients are refractory to standard anti-epileptic drug therapies (Huppke et al., 2007; Anderson et al., 2014). EEG findings are abnormal in almost all RTT patients (Hagne et al., 1989; Niedermeyer et al., 1986; Verma et al., 1986; Roche et al., 2019). Although there is no diagnostic pattern of RTT on EEG, several common abnormalities have been identified (Figure 1), and these evolve throughout development and pathophysiological progression (Glaze, 2005). A common EEG abnormality is the presence of generalized, rhythmic, medium voltage slow wave activity (3-5 Hz) which can be present during both wakefulness and drowsiness (Niedermeyer et al., 1986). Background slowing with increased EEG spectral power in the low frequency bands (i.e., increased delta power) is also a common finding (Roche et al., 2019). Bilateral-synchronous, scattered, or diffuse spikes and sharp wave activity is prevalent in roughly half of patients (Niedermeyer et al., 1986). Slow spike-wave complexes (1 – 2.5 Hz, typically during sleep) can be seen in roughly one quarter of patients (Niedermeyer et al., 1986), and

electrical status epilepticus of sleep (ESES) in approximately 15% (Nissenkorn et al., 2010). In addition, a majority of RTT patients display more than one clear EEG abnormality upon assessment (Niedermeyer et al., 1986).

Mouse Models of RTT Several mouse models expressing different types of humanized MECP2 mutations are currently available.

These include mutants expressing null alleles,

truncated alleles, and missense mutations (Katz et al., 2012). Seizure-related activity has been reported in many of these Mecp2 models, but with somewhat differing outcomes depending on mutation type and genetic background. The majority of work conducted to date has focused on either the Mecp2tm1.1Bird mouse strain (both males and females), which express a MeCP2-null allele (Guy et al., 2001), or the Mecp2tm2Bird mouse strain (males and females) which is an extreme MeCP2 hypomorph expressing approximately 5-10% normal MeCP2 levels (Guy et al., 2007; Kernohan et al., 2010; for review, see Katz et al., 2012). Both models show an age dependent progression in epileptiform discharge activity (Wither et al., 2018), with male MeCP2-null mice being more severely affected than heterozygous female MeCP2+/- mice (D’Cruz et al., 2010; Lang et al., 2013, 2014; Wither et al., 2012, 2013). The spontaneous discharges present in both male and female mice from these lines are generally short in duration (1-3 seconds in females and <20 seconds in males) (Figure 1), frequently correlate with behavioral pausing (particularly evident in the more severely affected male MeCP2-null mice) (D’Cruz et al., 2010; Eubanks, 2017; Lang et al., 2013; 2014; Wither et al., 2012;

2013), and display biophysical and pharmacological properties consistent with absence epilepsy (D’Cruz et al., 2010; Wither et al., 2018). In addition to this absence-like seizure phenotype, however, an additional type of seizure has been noted in mostly female MeCP2-heterozygous mice. Although much less studied than the absence-like activity highlighted above, these seizures are associated with behavioral (i.e. not captured on EEG to verify that they are truly epileptic) tonic or status-like convulsive activity, and often occur immediately following handling or cage-changing. Similar handling-induced behavioral seizures have also been reported for the related Mecp2tm1.1Jae mouse line (Chen et al., 2001) which also expresses a null Mecp2 allele, and in the Mecp2tm1.1Coyle mouse line which houses an R168X Mecp2 nonsense mutation (Schaevitz et al., 2013). This nonsense mutation may be functionally null, however, as truncated MeCP2 protein was not detected in an independently generated R168X mouse line (Mecp2R168XHuppke), which was not specifically assessed itself for epileptiform discharge activity (Brendel et al., 2011). In addition to these MeCP2-null allele models, spontaneous bilateral cortical discharges and myoclonic jerks have also been observed in male Mecp2tm1Hzo mice, which express a MeCP2 protein truncated at position 308 (Shahbazian et al., 2002) (Figure 1). In these mice, discharge activity is progressive, and only became overtly evident after about 6 months of age (Shahbazian et al., 2002). Similarly, spontaneous behavioral seizures were reported in a subset of male Mecp2tm1.1Joez mouse that express a clinically-relevant T158A Mecp2 missense mutation after approximately 5 weeks of age (Goffin et al., 2011), and handling-induced tonic-clonic seizures that often resulted in premature death were observed in heterozygous female mutant mice

expressing a related T158M Mecp2 missense mutation (Lamonica et al., 2017). The T158A and T158M mutations occur within the methyl DNA-binding motif of MeCP2, and each generate less stable MeCP2 proteins (roughly 50% hypomorphic) that have diminished ability to bind methylated DNA targets. In addition to these models, several other cell-type selective Mecp2 ablation models also exist that have allowed better identification of the excitatory and inhibitory circuitries underlying the observed seizure phenotypes. These models will not be expanded upon here for brevity, but are discussed in detail elsewhere (Eubanks, 2017; Katz et al., 2012).

Seizure Correlations Between RTT and Mecp2 Mouse Models Seizures and electrographic discharge patterns in these mouse models of RTT appear to directly recapitulate only a small subset of the seizure types seen in patients. While absence epilepsy is observed in some RTT patients (Niedermeyer et al., 1986; Pardal-Fernández et al., 2004), it is not a prevalent seizure type within the RTT population (Tarquinio et al., 2017). Absence seizures are, though, the predominant seizure at least under basal conditions in MeCP2-deficient mice (D’Cruz et al., 2010). However, the bilateral cortical slow spike-wave activity that associated with myoclonic jerks found in the Mecp2tm1Hzo mouse expressing the truncated MeCP2 protein (Shahbazian et al., 2002), and perhaps the largely uncharacterized handling-induced behavioral seizures seen in other lines, may better phenocopy the more common generalized tonic-clonic and complex partial seizure phenotype seen in RTT patients (Cardoza et al., 2011; Glaze, 2005; Pintaudi et al., 2010; Tarquinio et al., 2017).

Additional work is required to test this possibility. It is worth noting, though, that in all of the mouse RTT models examined to date, the lack of proper MeCP2 function has promoted the hyper-excitability of neural networks in the brain. It will be interesting to determine if the mechanisms underlying the network hyper-excitability in these mouse models are, in fact, common with those that cause the network hyper-excitability of patients.

CDKL5 Deficiency Disorder Clinical Presentation CDKL5 deficiency disorder (CDD) is a rare genetic condition frequently characterized by epileptic encephalopathy, with early onset epilepsy and severe cognitive impairments commonly evident (Archer et al., 2006; Demarest et al., 2019; Evans et al., 2005; Olson et al., 2019; Weaving et al., 2004). While CDD was initially considered the "early seizure variant" of RTT, subsequent clarification through the study of larger cohorts determined that CDD is clinically distinct (Fehr et al., 2013). The CDKL5 gene resides on the X chromosome, making CDD an X-linked disorder (Tao et al., 2004; Weaving et al., 2004). Although some boys do present with CDD, like RTT, CDD affects mostly females, and almost all of these patients are heterozygous for a CDKL5 mutation (Olson et al., 2019). Several different mutations of the CDKL5 gene have been identified that can be causal for the condition (Hector et al., 2017). The incidence of CDD is approximately 1 in 42,000 live births (Symonds et al., 2019). Many patients with CDD show typical findings associated with epileptic encephalopathies. Seizures and epileptic spasms present within the first few months of

life, and in a subset of patients this is accompanied by the hypsarrhythmia pattern on EEG (Figure 2) (Demarest et al., 2019). These patients also tend to have severe cognitive and developmental impairment (Kalscheuer et al., 2003; Scala et al., 2005; Tao et al., 2004; Weaving et al., 2004), and like RTT patients often display hypotonia, stereotypy, and loss of speech (Kalscheuer et al., 2003). As the patients age many will develop absence, myoclonic, tonic, or tonic-clonic seizures (Evans et al., 2005; Guerrini & Parrini, 2012; Kalscheuer et al., 2003), which are frequently drug resistant (BahiBuisson et al., 2008; Mei et al., 2010). Hypsarrhythmia may be found in approximately 38% of all CDD patients, and roughly half of patients presenting with epileptic spasms (Demarest et al., 2019). No diagnostic EEG pattern currently exists, and the EEG findings are heterogeneous and vary with age. Background slowing is a common EEG finding (Archer et al., 2006; Grosso et al., 2007; Melani et al., 2011), and in some cases a burst-suppression pattern is seen (Melani et al., 2011) (Figure 2). Interictal epileptiform activity includes bi-temporal paroxysmal activity, and focal and multi-focal spikes and sharp waves are frequently observed (Archer et al., 2006; Melani et al., 2011) (Figure 2). Non-convulsive status epilepticus events have also been reported (Evans et al., 2005).

Mouse Models of CDD Network hyper-excitability and seizure activity have been assessed in two mouse models of CDD that express a null allele (Wang et al., 2012), and in one that expresses a clinically relevant R59X CDKL5 nonsense mutation (Tang et al., 2019; Yennawar et al., 2019). Under basal conditions, none of these models display either overt behavioral

seizures or discharge activity on cortical EEG examinations (Amendola et al., 2014; Wang et al., 2012). However, excitatory network hyper-sensitivity has been reported in male mice expressing a null Cdkl5 allele, and increased seizure severity following systemic administration of NMDA was observed (Okuda et al., 2017). In addition, a recent study found male Cdkl5R59X mice to display decreased latency times to seizure onset following pentylenetetrazole administration compared to male wild-type mice (Yennawar et al., 2019). While work continues on these and newer CDD models that have also now been generated, the results to date indicate CDKL5 deficiency in mice is sufficient to promote network hyper-excitability, but not sufficient - at least on the genetic backgrounds thus far examined (mostly C57Bl/6) - to promote seizures under baseline conditions.

Seizure Correlations Between CDD and CDKL5 Mouse Models The lack of overt seizure activity in the different CDKL5-deficient mouse models was surprising given the high prevalence of severe spontaneous epilepsy forms in CDD patients. While only a limited number of studies have been reported to date, the data thus far indicate that CDD mouse models do not recapitulate the most cardinal clinical and electrographic seizures commonly seen in CDD patients. Further experimentation is needed to determine whether EEG findings may be present under specific conditions, or perhaps in selectively targeted conditional knock out mouse systems. However, like in the different MeCP2-deficient mouse models of RTT, the presence of hyper-excitable brain networks in CDKL5-deficient mice as indicated by their shorter latencies to seizure onset and increased severity to convulsant treatment does highlight the importance of

proper CDKL5 function in the establishment of normal network excitatory / inhibitory balance.

Fragile X Syndrome Clinical Presentation FXS is one of the most common genetic neurodevelopmental disorders (Kidd et al., 2014), with prevalence rates of the full mutation estimated at 1.4 per 10,000 males, and 0.9 per 10,000 females (Hunter et al., 2014). A full mutation is defined as an expansion of 200 or more CGG repeats within the 5’UTR of the X-linked FMR1 gene (Verkerk et al., 1991). Methylation of these CGG repeats causes epigenetic silencing of FMR1 expression, and thus the lack of its protein product FMRP is causal for FXS (Pieretti et al., 1991). Roughly half of all FXS patients show paroxysmal abnormalities on EEG, with approximately 20% of FXS patients developing a form of epilepsy (Musumeci et al., 1999; O’Leary & Benke, 2017; Sabaratnam et al., 2001). Amongst these individuals, multiple seizure types have been observed, which include focal aware seizures (FAS, previously known as simple partial), FIAS, tonic-clonic, febrile seizures, and rarely status epilepticus (Musumeci et al., 1999). While many FXS patients respond to anti-epileptic drugs, approximately 25% of patients are refractory and will continue to have seizures into adulthood (Musumeci et al., 1999; O’Leary & Benke, 2017). EEG abnormalities in pediatric patients are largely consistent with childhood epilepsy with centrotemporal spikes (CECTS, previously known as Rolandic epilepsy) (Figure 3) (Berry-Kravis, 2002; Incorpora et al., 2002; O’Leary & Benke, 2017). Although interictal

EEG background activity can appear relatively normal, particularly during wakeful periods (Figure 3), background slowing or slowing of the posterior dominant rhythm, increased generalized rhythmic theta activity, focal spikes, and multi-focal or diffuse spike waves have also been reported on EEG, particularly during periods of sleep ( Musumeci et al., 1999; Heard et al., 2014; Incorpora et al., 2002; Sabaratnam et al., 2001) (Figure 3).

Models of FXS Several models of FXS have been generated, which include classic knockout (KO), conditional knockout (CKO), and knock-in (KI) mice. The first Fmr1-KO mouse (Fmr1tm1Cgr) incorporated a neomycin cassette into exon 5 of the Fmr1 gene, and this interruption abrogated the expression of functional FMRP (Consorthium et al., 1994). Two additional KO models, the Fmr1-KO2 mouse (deletion of Fmr1 exon 1) and the Fmr1-CKO mice (loxP-flanked neo cassette introduced into Fmr1 promoter region) have been generated, and mice from each line lack Fmr1 mRNA and FMRP protein expression (Mientjes et al., 2006). As the human condition involves CGG repeat expansion, two different KI lines of mice that house CGG repeat units have also been developed. The first line replaced the natural 8 CGG repeats in the mouse gene with 98 repeats to copy a pre-mutation form of the human gene seen in some patients (Bontekoe et al., 2001), while the second introduced an insertion of approximately 120 CGG-CCG repeat units in exon 1 to better recapitulate the expansions associated with a full human mutation (Entezam et al., 2007). Both KI models show decreases in FMRP expression, but to varying degrees between brain regions (Entezam et al., 2007;

Bontekoe et al., 2001). Additional mice carrying longer CGG repeats have also now been generated (Brouwer et al., 2007) which similarly show decreased FMRP protein. Unlike the human condition, however, none of these KI mice reliably show hypermethylation of the inserted CGG repeats (Brouwer et al., 2007; Entezam et al., 2007), indicating the hypomorphic effect on FMRP likely occurred through mechanisms distinct from those seen in typical FXS patients. Whether the different mechanisms between mouse and human could also influence phenotypic outcomes such as epilepsy or network hyper-excitability remains unclear. Spontaneous baseline seizures have not been reported in any of the FMR1 KO mouse models to date (Figure 3), although what has been reported to date comes largely from visual observations that were not accompanied with EEG assessments (O’Leary & Benke, 2017). Audiogenic seizures, however, have been observed in different strains of Fmr1 KO mice, and can be reproducibly induced by administering a 115-125 dB auditory stimulus (Musumeci et al., 2000). These seizures follow a strict course, which begins with running, then progresses to clonus, which is followed by tonus, which can be followed by respiratory arrest and in some cases death (Musumeci et al., 2000). Male Fmr1 KO mice showed the highest susceptibility to audiogenic seizures at 45 days of age, while female Fmr1 KO mice were most susceptible at 22 days (Musumeci et al., 2000). While overt alterations in baseline EEG are not evident in Fmr1 KO mice (Figure 3), more detailed examinations of cortical EEG frequency power has revealed some notable abnormalities, which include increased power in the gamma band has been reported in the frontal and auditory cortex (Lovelace et al., 2018; Wen et al., 2019), as

well as reductions in evoked gamma synchronization (Lovelace et al., 2018). Optogenetic-induced excitation of layers 2 and 3 of the auditory cortex of Fmr1 KO mice also expressing channel rhodopsin 2 revealed hyper-excitability and increased gamma band power in layers 2, 3, and 5 (Goswami et al., 2019). While not necessarily epileptogenic, these features suggest that increased network hyper-excitability does exist in the Fmr1-KO brain, which by itself could predispose specific circuitries to stimulus-induced seizures.

Additional mouse models displaying lineage-specific

deletion of Fmr1 have also been generated (Mientjes et al., 2006), but will not be covered here.

Seizure Correlations Between FXS and FMR1 Mouse Models From a high-altitude level, the mouse models of FXS thus far examined have not phenocopied the most common seizure and/or EEG patterns that are present in FXS patients that have an epilepsy co-morbidity. Behavioural seizures have not been reported in these models in the absence of a specific stimulus, and no spontaneous discharge activity has been observed in either cortical or limbic circuitries by EEG recording (Lovelace et al., 2018; Wen et al., 2019). However, it is clear that these mouse models do possess a hyper-excitable network phenotype, as seizures can be reproducibly induced by external stimuli such as auditory cuing. The mechanisms through which this network sensitization arises are likely multifactorial (for review, see Rotschafer & Razak, 2014), but delineating the mechanisms for the network hyperexcitable phenotype may provide translational targets for future interventions.

Dravet Syndrome Clinical Presentation Severe myoclonic epilepsy of infancy (SMEI, also known as Dravet syndrome), was initially reported by Charlotte Dravet in 1978 (see Dravet et al., 2005). It is a rare, genetic, epileptic encephalopathy that affects children generally within the first year of life (Richards and Petrou, 2017). Otherwise healthy children will typically present with acute febrile seizures, which tend to increase in both duration and frequency as they age. The developmental regression characteristic of the encephalopathies will then typically present in the second year of life as the seizure phenotype progresses (Dravet, 2011; Richards and Petrou, 2017). The majority of Dravet syndrome patients (approximately 90%) have de novo mutations in the alpha1-subunit of the voltage gated sodium channel (SCN1A). Approximately 85% of these SCN1A alterations are single mutations, but some copy number variants have also been identified (McTague et al., 2016). Epidemiological studies suggest Dravet syndrome has an incidence rate of between 1 in 15,000 to 1 in 22,000 (Bayat et al., 2015; Wu et al., 2015). While mutations of SCN1A gene are the most common cause for Dravet syndrome, mutations involving the SCN1B sodium channel subunit gene (Wallace et al., 1998), the GABAA receptor γ2 subunit gene (GABRG2) (Harkin et al., 2002; Macdonald et al., 2012), and the GABAA receptor 1 subunit gene (GABRA1) (Carvill et al., 2014) are also recognized causes for clinical Dravet syndrome. Epilepsy in Dravet syndrome is characterized by repeated and prolonged generalized or lateralized clonic and tonic-clonic seizures (febrile and afebrile) with onset within the first year of life. Over time, multiple seizure types arise alongside the

generalized convulsions, such as focal, myoclonic and atypical absence seizures. Myoclonus and ataxia may also present during interictal periods, and generalized spikewave discharge is more prevalent during periods of myoclonus (Bureau & Bernardina, 2011; Dravet, 2011; Wolff et al., 2006). Interictal EEG in infancy and the early disease state may appear largely normal, however, the post-ictal EEG pattern may show lateral or diffuse slowing or spike waves. After the second year of age, progressive increases in generalized paroxysms (generalized spike waves or fast polyspikes, typically in the frontocentral regions) often emerge on EEG (Figures 4-6). Many patients also display asynchronous focal and multi-focal abnormalities such as fast spikes or polyspikes (Figure 4; Figure 5), typically in the frontocentral or centrotemporal regions (Figure 4; Figure 6). The inter-ictal background EEG remains normal in approximately half of patients, while slowing and disorganization are often evident in other patients (Akiyama et al., 2010; Bureau & Bernardina, 2011; Dravet, 2011). In patients with persistently normal background, a pattern of markedly increased theta activity can be seen in the central regions, typically during eye closure (Bureau & Bernardina, 2011).

Dravet Syndrome Models Several mouse models of Dravet syndrome have been generated that mirror several of the genetic abnormalities seen in human patients. These include mice expressing different mutations within their Scn1a, Scn1b, Gabr2, and Gabr1 genes (Richards & Petrou, 2017, p. 52).

For SCN1A, several lines of mutant mice have been created. These include different lines of KO and CKO mice, and a line expressing an R1407X nonsense mutation seen rarely in some Dravet syndrome patients. Homozygous KO of Scn1a in mice was found to be perinatal lethal, with lifespans rarely exceeding 15 days (Yu et al., 2006). Heterozygotes mutant Scn1a KO mice, however, can live into adulthood, although there is a higher than normal risk for sudden death both before and after weaning that is influenced by genetic background (Yu et al., 2006). These heterozygous Scn1a mice display spontaneous electrographic and behavioral seizures on video EEG, some inter-ictal epileptiform activity (Yu et al., 2006) (Figure 4), and are sensitive to thermally-induced seizures (Oakley et al., 2009). Background EEG is otherwise typically normal, with low amplitude baseline recorded (Figure 4). Consistent with a loss of SCN1A function, these mice also show decreased sodium channel currents overall, and particularly within hippocampal GABAergic interneurons (Yu et al., 2006). Consistently, mice homozygous for an R1407X nonsense mutation in their Scn1a gene develop spontaneous clonic, and tonic-clonic behavioral seizures by postnatal day 12, and few of these homozygous mice lived longer than postnatal day 16. The similarities with this Scn1aR1407X nonsense mouse to the homozygous complete Scn1a KO mice are not surprising, as the R1407X nonsense mutation does not allow for the generation of a functional SCN1A protein (Ogiwara et al., 2007). Consistent with the full Scn1a KO mice, background EEG activity in homozygous Scn1aR1407X was similar to wildtype. Ictal EEG in homozygous Scn1aR1407X mice showed 1-4 Hz polyspike and wave discharges. Heterozygous Scn1aR1407X mouse developed spontaneous seizures and showed high

rates of sporadic deaths after post-natal day 18, with only about 60% of the mice surviving to three months of age (Ogiwara et al., 2007). An Scn1b KO mouse line has also been generated (Chen et al., 2004). Mice homozygous null for Scn1b display significantly decreased viability, with most mice dying between postnatal day 13 and postnatal day 26 (Chen et al., 2004). In homozygous null Scn1b mice that reach postnatal day 10, frequent and severe generalized myoclonic seizures are evident, and their corresponding cortical EEG patterns display high-voltage rhythmic polyspikes (that occur during both day and night). These mice have generally normal background EEG patterns, but do show occasional interictal spikes (Chen et al., 2004). Interestingly, the delayed induction of this Scn1b null mutation in mice that had previously developed normally into adulthood resulted in the same spontaneous seizure phenotype and mortality within 20 days of deletion (O’Malley et al., 2019). In contrast, mice heterozygous for Scn1b did not display this spontaneous epileptiform seizure phenotype – heterozygous Scn1b mice live normal lifespans and show no difference in latency to onset or seizure severity following pentylenetetrazole injection (Patino et al., 2009). These latter results indicate a single functional Scn1b allele is sufficient to provide the necessary beta subunits required for proper sodium channel function. In addition to the sodium channel SCN1A and SCN1B Dravet syndrome models, mouse models mirroring Dravet syndrome caused by less common mutations of the GABR2 and GABR1 subunit encoding genes have also been generated. Mice homozygous for a nonsense mutation of Gabr2 (Q390X) are severely affected and do not survive past postnatal day 0 (Kang et al., 2015). This mutation does generate a

detectable truncated 2 subunit lacking its terminal 78 amino acids, indicating this nonsense mutation likely does not activate nonsense mediated mRNA decay systems (Kang et al., 2015). Mice that are heterozygous for this Q390X nonsense mutation are viable, however, but by 4 weeks of age began to show heightened rates of spontaneous death (Kang et al., 2015). These heterozygous mice were found to develop a severe epilepsy phenotype by approximately post-natal day 19, though, in which tonic-clonic seizures were evident and interictal epileptiform activity was readily detectable on EEG when the mice were between 8-16 weeks of age (Kang et al., 2015) (Figure 5). In addition, these heterozygous Q390X mice also displayed heightened sensitivity to thermally-induced myoclonic jerks that were associated with spike-wave discharges (Warner et al., 2017). For Gabar1, mice that lack functional 1 subunits have been generated (Vicini et al., 2001). Mice homozygous for this mutation show high mortality rates shortly after post-natal day 19. Heterozygous mice are viable, but show a significantly elevated incidence of spontaneous death. Synchronized video-EEG analysis of these heterozygous mice revealed the presence of slow cortical spike and wave discharges of 3-5 seconds (Figure 6) that were coincident with behavioral arrest. Pharmacologically, these discharges were blocked by the anti-absence drug ethosuximide (Arain et al., 2012). Collectively, these features indicate the heterozygous deletion of the Gabr1 subunit gene is sufficient to cause an absence-like phenotype in mice, but is not sufficient to induce the more typical Dravet-like seizures present in patients expressing mutations in GABR1.

Seizure Correlations Between Dravet Syndrome and Different Dravet Mouse Models The different SCN1A-related models of Dravet syndrome are fairly consistent between each other, and phenocopy several aspects of the human condition. It is important to note that different SCN1A mutations may cause Dravet syndrome pathogenesis through distinct mechanisms, with both haploinsufficiency and dominant negative modes of action implicated for specific SCN1A mutations (Bechi et al., 2012). This clearly has bearing on the utilization of mouse models, as homozygous KO mice would not likely recapitulate the pathogenic mechanisms stemming from a mutation leading to haploinsufficiency, and heterozygous KO mice may not recapitulate dominant negative pathogenic mechanisms.

With that caveat noted, however, most of the

available SCN1A mutant mice develop spontaneous seizures at young ages, and interestingly display relatively normal background EEG activity. Approximately half of Dravet syndrome patients also display relatively normal background EEG patterns, and thus these mouse models may recapitulate the electrophysiological aspects of this subset of patients. These Scn1a mutant mice are also susceptible to thermally induced seizures (both clonic and tonic-clonic), which may be a recapitulation of the febrile seizures frequently observed in Dravet syndrome. Consistently, the Scn1b and Gabr2 mice also display spontaneous tonic-clonic seizures and interictal discharges, but also have largely normal background EEG patterns. However, the absence epilepsy phenotype of mice with the Gabr1 mutation does not phenocopy the primary seizure phenotypes seen in Dravet syndrome patients that have GABR1 mutations. Like with RTT, however, the presence of hyper-excitable networks does illustrate that the loss of

GABR1 function is sufficient to promote pathogenic-like changes in systemic function, but the end-point in mice does not lead to the same manifestations as observed in patients.

Ohtahara Syndrome Clinical Presentation Ohtahara Syndrome (OS) is a rare epileptic encephalopathy, first described by Shunsuke Ohtahara in 1976 (Ohtahara et al., 1976). No precise measure or study of the epidemiology of OS has been reported to date, although a study of 2378 children with epilepsy in Japan found only a single case of OS (Oka et al., 1995) indicating it has a very rare overall occurrence rate. OS can originate from different genetic causes, as several single gene mutations have been identified as sufficient to be causal in different patients. While the search for additional genetic causes continues, mutations occurring within the autosomal syntaxin-binding protein 1 gene (STXBP1), the X-linked aristaless related homeobox (ARX) gene, the autosomal 2 subunit of the voltage-gated sodium channel (SCN2A), and the autosomal voltage-gated potassium channel subfamily Q member 2 (KCNQ2) genes are now recognized individual causes for OS (Ekşioğlu et al., 2011; Kato et al., 2007; Nakamura et al., 2013; Otsuka et al., 2010; Saitsu et al., 2012; Saitsu et al., 2010). Typically, OS onset occurs within the first few months of life, and is often seen within the first ten days or even possibly in utero (Clarke et al., 1987; Yamatogi and Ohtahara, 2002). The most common seizure type in OS is lateralized and/or generalized tonic seizures. Infants may also present with myoclonic jerks or focal or multifocal clonic

seizures during the neonatal period. Seizures are very frequent and occur during both periods of wakefulness and sleep. Frequently, these seizures are highly drug resistant. After seizure onset, patients typically become hypoactive, display severe hypotonia, and lose visual alertness. Mortality is high within the first two years of life, and patients who live into later years often develop other epilepsy conditions such as epileptic spasms or Lennox-Gastaut. Severe cognitive and motor deficits appear coincident with the progression of seizures (Clarke et al., 1987; Saitsu et al., 2012; Yamatogi and Ohtahara, 2002). On EEG examination, OS characteristically shows regular interictal patterns of burst-suppression, and ictal desynchronization with sudden flattening or low voltage fast activity (Figures 7-9). Bursts of high voltage slow wave activity and intermixed multifocal polyspikes lasting 1-3 seconds alternate with 2-5 seconds of flattening of the background on scalp EEG examination (Figures 7-9). The burst-to-burst time is typically 5-10 seconds. Some patients may show some subtle asymmetry, and some may have periodic hypsarrhythmia (Clarke et al., 1987; Yamatogi and Ohtahara, 2002).

Models of OS Different lines of STXBP1 mutant mice have been generated. These include heterozygous KO and missense alterations that genocopy mutations seen in individual patients (Hager et al., 2014; Kovačević et al., 2018; Miyamoto et al., 2017; Orock et al., 2018; Verhage et al., 2000). To date, epilepsy-related investigations have only been conducted on two KO lines. Mice heterozygous for Stxbp1 were viable, but were found to have myoclonic-like “twitches” (approximately one per hour) and “jumps”

(approximately one per hour and a half) that emerged between 8 to 12 weeks of age. Often these events occurred during periods of sleep. EEG recordings in the cortex and CA1 hippocampal subfields of these mice revealed the presence of frequent highamplitude spike-wave discharges of approximately 7 Hz with typical durations of 1.5 – 2 seconds (Figure 7), which were partially suppressed by leviteracetam (Kovačević et al., 2018). Collectively, these phenotypes recapitulate at least some of the pathogenic features seen in most OS patients with STXBP1 mutations. A missense Kcnq2 loss-of-function mutation (A306T) mouse model has also been generated. Mice homozygous for this Kcnq2A306T mutation are severely affected, and show frequent spontaneous, generalized tonic-clonic seizures that begin early in life and continue into adulthood (Singh et al., 2008). These homozygous Kcnq2A306T mice also display a high risk for spontaneous death, as only about 10% survive past about 1 month of age (Singh et al., 2008). EEG assessments of homozygous Kcnq2A306T mice that did survive to 3 months revealed the presence of both interictal cortical discharges and generalized ictal events (Figure 8). Mice heterozygous for the Kcnq2A306T mutation were less severely affected, but did show reduced thresholds for electroconvulsive stimulation-induced seizures, indicating the heterozygosity is sufficient to promote hyper-excitable networks. In addition to this missense mutation, complete KCNQ2 KO mice have also been generated. Mice homozygous null for Kcnq2 ablation are not viable, and typically die before postnatal day 2 (Watanabe et al., 2000). Mice heterozygous for Kcnq2, however, are viable, survive until full adulthood, and do not display baseline spontaneous epileptic discharges or overt behavioral seizures (Watanabe et al., 2000). However, these heterozygous Kcnq2 mice do show decreased

latency to seizure onset following pentylenetetrazole injection indicating the presence of hyper-excitable networks (Watanabe et al., 2000). A related strain of Kcnq2 mutant mice expressing a Y284C missense mutation has also been generated. Similar to heterozygous Kcnq2 KO mice, mice heterozygous for the Kcnq2Y284C missense mutation do not show spontaneous behavioral seizures, but do show heightened seizure severity scores following kainic acid injection compared to wild-type (Ihara et al., 2016). There have also been several mouse lines developed that express null, missense, or triplet expansion mutations of the X-linked Arx gene. Male hemizygous Arx-null mice display aberrant brain formation and neuronal morphologies at newborn stages, but assessments of seizure or discharge activities have yet to be reported. Likewise, these assessments remain to be conducted as well in heterozygous female Arx-null mice (Kitamura et al., 2002). Additional lines of mice expressing clinicallyrelevant P353L and P353R missense mutations of Arx have also been generated. Most male ArxP353R mice are severely affected, and die by postnatal day 1 (Kitamura et al., 2009). However, some male ArxP353L mice can survive longer than 6 months of age, and approximately 10% of those mice were found to display spontaneous tonic seizures in early adulthood. In addition, these male ArxP353L null mice displayed increased sensitivity to bicuculline-induced seizures compared to WT controls at both 1 and 3 months of age (Kitamura et al., 2009). In addition to the Arx KO and missense mutation mice, different groups have also generated mutant mice that house poly-alanine expansions within the ARX coding sequence. These expansions recapitulate a mutation seen in some human patients

(Poirier et al., 2008; Price et al., 2009; Kitamura et al., 2009). In one line, a triplet expansion was introduced at position 304 that added seven alanine amino acids into the ARX protein (Price et al., 2009). Male mice expressing this mutation showed spontaneous myoclonic spasms as early as postnatal day 7 (Price et al., 2009). Cortical EEG analysis of these male mice between postnatal days 11 – 21 showed repetitive periods of high voltage slow wave activity that were followed by modest flattening of background EEG activity, but with an increase in periodic high frequency rhythmic activity. Myoclonic jerks were also observed, and were associated with the period of partial EEG background flattening (Price et al., 2009). Subjects at this age also showed multifocal high amplitude cortical spikes and sharp waves, but these were not associated with flattening of the background or any changes in frequency power (Price et al., 2009). In older mice (3.5 – 10 weeks) three types of spontaneous electrographic seizures were reported: 1) frequent multifocal single spike and sharp wave patterns, 2) bursts of 6 Hz spike and wave events associated with behavioral arrest (up to 4 seconds) (Figure 9), and 3) generalized flattening of the background along with the appearance of low voltage fast activity, followed by generalized high amplitude and frequency spikes and polyspikes, ending with prolonged background attenuation (Price et al., 2009). In addition to this GCG expansion line, a different poly-alanine expansion ARX mouse has been generated. In this line, the GCG expansion encoding for seven alanine amino acids was inserted into position 330 of the ARX protein coding segment (Kitamura et al., 2009). This insertion caused the expressed ARX protein to be hypomorphic (~50%), which likely affected the functional activity levels of ARX within

cells (Kitamura et al., 2009). 70% of male mice expressing this mutation displayed spontaneous seizures by approximately 1 month of age, which involved a pattern consisting of tonic-clonic seizures, followed by running fits, that was then followed by a loss of postural control and movement (Kitamura et al., 2009). EEG recordings from different brain regions in these mice did not detect interictal spiking activity, although diffuse ictal spike bursts were detected in different regions that were followed by a flattening of background EEG activity (Kitamura et al., 2009). These ictal-onset EEG from the hippocampus, striatum and frontal cortex of these mice showed spiking activity that evolved into bursts of spikes (20–30 Hz) in the hippocampus (approximately 10 – 15 seconds), followed by continuous high voltage spikes in the striatum (approximately 60 seconds). This activity was followed by a period of long-lasting low voltage activity with rhythmic, synchronous theta-like waves (Kitamura et al., 2009).

OS Seizure Correlations Some models of OS do appear to capture many of the cardinal human phenotypic features seen in patients, while others were less successful in recapitulating these clinical features. While studies are ongoing, recent work with Stxbp1 mutant mice have shown behavioral seizures, epileptiform activity on EEG, and myoclonic events during sleep that are present in many OS patients with STXBP1 mutations. In contrast, the heterozygous mutations in the Kcnq2 gene in mice did not produce spontaneous seizures in mice. This differs from OS, where de novo spontaneous heterozygous mutations of KCNQ2 are a recognized cause of OS. However, these heterozygous mice did display neuronal hyperexcitability as shown by an increased sensitivity to PTZ,

confirming a heterozygous loss of Kcnq2 is sufficient to affect neural network excitatory / inhibitory balance. While homozygous A306T Kcnq2 mutations did lead to spontaneous generalized tonic-clonic seizures, they did not phenocopy the typical electrographic patterns associated with OS expressing this mutation. In general, though, the Arx mutations engineered in mice appear to better phenocopy several aspects of the electroclinical phenotype of OS. The GCG insertions at position 330 was sufficient to cause spontaneous seizures, but curiously was not associated with any interictal epileptiform activity (Kitamura et al., 2009). However, a similar mutation that introduced GCG tracts at position 304 promoted an EEG pattern in mice with electrodecremental responses that were associated with myoclonic jerks and multifocal cortical spikes and sharp-waves (Price et al., 2009). These findings may be similar to the burst suppression and tonic spasms seen in infants with OS, but additional investigation is needed to further validate this possibility.

Discussion Different mouse models of neurodevelopmental disorders and epileptic encephalopathies have had some success in recapitulating the behavioral and electrographic phenotypes seen in human patients. There is an interesting, and not entirely

unexpected,

correlation

between

the

prevalence

and

severity

or

seizures/epilepsy in certain gene specific disorders and their model counterparts; often but not always relating to the severity of the clinical condition. Models of OS, for example, are much more overtly affected than models of FXS with respect to seizures and EEG anomalies seen in patients, for example. However, in some cases the mouse

models fail to recapitulate these features – even though they can be quite severe in many of the patients. The lack of seizures and spontaneous epileptiform discharges in complete null CDKL5-deficient mice is a good example. Some of this discordance could be due to genetic background modifying factors that can influence the severity of the symptom. Most studies conducted to date on the different mouse models relied heavily on a C57Bl/6 genetic background, which is known to be more seizure resistant than other genetic backgrounds (Schauwecker, 2002; Löscher et al., 2017). It will be of interest to examine whether specific models would phenotypically differ if maintained on distinct or mixed genetic backgrounds that might better reflect what would be seen in the patient population. Background or epigenetic considerations notwithstanding, some of the Dravet syndrome and OS mouse models reviewed here did appear to capture aspects of both the behavioral and electrographic features of the seizures seen in patients with these disorders. There is clear evidence of network hyperexcitability in models of these conditions, with profound background EEG changes and interictal epileptiform activity reported. Specific EEG findings in these models – such as burst-suppression-like discharges in the ARX OS models have good face validity to go along with strong construct validity. Moreover, the spontaneous seizures frequently found in these models resemble what is seen in patients, as well as the varying seizure types that are displayed (i.e., spasms, tonic-clonic, absence, etc) that also have also been observed in different patients. At the other end of the spectrum, however, there is an interesting divergence between human CDD and its mouse model counterparts – even though the mice

generated were null for CDKL5. CDD typically presents with severe seizures and epileptic encephalopathy in infants. These seizures continue throughout development. This cardinal feature of CDKL5 mutation in humans in not readily evident in mice – to date, the different mouse models of CDD that have been examined have not shown any spontaneous behavioral or electrographic seizures, and no epileptiform discharges, on EEG. It is possible, though, that these mutations in humans lower seizure thresholds to a point where spontaneous activities are seen, while in mice the seizure threshold change is insufficient to promote such spontaneous epileptic phenotypes. This would be consistent with the increased sensitivity of CDKL5-deficient mice to both NMDA and PTZ induced seizures, and FX mice to audiogenic seizures. This increased seizure sensitivity illustrates that hyper-excitable networks in these models do exist, but it remains unclear at present why the more severe seizure phenotype seen in many patients do not emerge in the mouse models. It is not because mice in general are somehow protected from developing these types of perinatal seizures – they do in the OS and Dravet syndrome models – so clearly more investigation is needed to better understand the discordance between the more severe seizure phenotype in humans and the lack thereof in CDD models. Models of FXS also fail to recapitulate the primary seizure phenotype that is seen in a subset of FXS patients. As with the RTT and CDD mouse models, network hyperexcitability is also seen in these FXS mouse models, but no spontaneous seizures or epileptiform discharges have been reproducibly reported to date. Curiously these models are highly susceptible to audiogenic seizures, although what aspect of the human phenotype these stimulus-induced seizures would model is unclear. However, it

is worth noting that while the rate of epilepsy is substantially higher in the humans with FXS compared to the general population (approximately ~20% versus ~1%), the majority of FXS patients do not have seizures/epilepsy. It may be that the models reviewed here capture neurodevelopmental aspects of FXS seen in the approximately 80% of patients who do not develop epilepsy, which as discussed above may involve specific genetic background modifiers or epigenetic alterations that hinder or allow epileptogenesis. As above, additional studies will be required to properly investigate these issues. Finally, one of the major driving forces for generating the different mouse models of these conditions in addition to delineating mechanistic causes of pathogenesis is the potential for the model to be used for pre-clinical translational investigations. In this regard, a strong argument can be made that each of the models discussed here have value – but there must be reason applied for whether or not the targeted symptom for the given intervention is of strong or weak predictive value. Different symptoms within the same mouse model could fall into different ends of this spectrum with respect to patients. It may be that an intervention that improves latency to seizure onset in a pentylenetetrazole model, for example, would have strong efficacy on tonic-clonic or myoclonic seizures in a patient, but the easiest path for preclinical efficacy translating into clinical trials would involve those studies where the targeted phenotype showed the best face validity to a key comorbidity of the patients. In the absence of a perfect correlation between mouse model and patient one must use the model available - but choosing an end-point bearing the best face validity to patients for interrogated would be strongly recommended.

Acknowledgments The authors have no conflicts of interest to declare. M.F. would like to acknowledge a Fellowship from the Department of Pharmacology and Toxicology, of the University of Toronto. This work was supported by a project grant from the Ontario Brain Institute EpLink epilepsy research program, and an operating grant from the Canadian Institutes of Health Research MOP125909.

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Figure Legends Figure 1: Rett Syndrome. (A) Generalized medium-to-high amplitude spikes, polyspikes, and spike-waves in a 4.5 year old RTT female patient. (B) Multifocal spikes in a 4.75 year old female patient. (C) Focal epileptiform activity in the right centroparietal area of a 4 year old female patient. Reproduced with permission from Verma et al., 1986. (D) Cortical EEG in a female heterozygous Mecp2tm1.1Bird mouse showing absence-like spike-wave discharge at 3 months and 19 months of age. Reproduced with permission from Wither et al., 2018. (E) Top: Bilateral cortical spike-wave discharge during a spontaneous myoclonic seizure in an adult male Mecp2tm1Hzo mouse. Spike-wave events like these were associated with myoclonic jerks. Bottom: Normal interictal EEG in a male Mecp2tm1Hzo mouse. Reproduced with permission from Shahbazian et al., 2002. Figures have been modified for brevity, for complete details see Verma et al., 1986; Wither et al., 2018; and Shahbazian et al., 2002.

Figure 2: CDKL5 Deficiency Disorder. (A) Interictal burst suppression pattern in a 7 month old female patient. Reproduced with permission from Melani et al., 2011. (B) Interictal sleep EEG showing modified hypsarrhythmia with bursts of generalized polyspikes and spike-waves and an absence of normal sleep pattern in a 10 month old female patient. (C) Interictal sleep EEG showing diffuse high-amplitude delta waves with intermixed spikes, polyspikes, and spike-waves and the absence of normal sleep

pattern in a 9 year old female patient. (D) EEG during wakefulness in a 9 year old female patient showing EEG discharges correlated with myoclonic events. Panels B, C, and D reproduced with permission from Bahi-Buisson et al., 2008. Figures have been modified for brevity, for complete details see Melani et al., 2011; and Bahi-Buisson et al., 2008.

Figure 3: Fragile X Syndrome. (A) Left: Interictal EEG during wakefulness with normal background activity and an isolated spike in the left centrotemporal region in a male patient. Right: Interictal EEG during sleep showing spikes and spike-wave discharges in the left centrotemporal region of the same male patient. Reproduced with permission from Musumeci et al., 1999. (B) EEG recordings in the auditory and frontal cortex of wildtype (left) and Fmr1 KO (right) mice at post-natal day 21 show relatively normal baseline activity in each region. Reproduced with permission from Wen et al. 2019. Figures have been modified for brevity, for complete details see Musumeci et al., 1999; and Wen et al., 2019.

Figure 4: Dravet Syndrome: (A) Interictal EEG in a 17 month old patient with an unreported gene mutation. Left: EEG during awake state showing bursts of spike-waves (induced by eye opening/closing). Middle: Epileptiform discharge event seen during drowsiness. Right: Diffuse spike-wave event observed during sleep. Reproduced with permission from Bureau & Bernardina, 2011. (B) Cortical EEG from a wild-type showing normal activity (traces designated +/+); from an Scn1a+/- KO mouse (traces designated +/-) showing a period of relatively normal background activity; from an SCN1A+/- mouse during a spontaneous seizure event (trace designated +/- Ictal) with behavioural correlates: * left hindlimb flexion, straub tail, and myoclonic jerk, ** bilateral forelimb clonus and head bobbing, *** relaxed muscle tone and end of seizure; and from an SCN1A+/- mouse showing an interictal period with clear epileptiform discharges (designated +/- Interictal). Reproduced with permission from Yu et al., 2006. Figures have been modified for brevity, for complete details see Bureau & Bernardina, 2011; and Yu et al., 2006.

Figure 5: Dravet Syndrome: (A) Interictal scalp EEG recording in a male patient with the GABR2 form of Dravet Syndrome. Shown are patterns of diffuse background slowing and irregular, generalized epileptiform activity. Reproduced with permission from Shen et al., 2017. (B) Cortical EEG from a GABR2+/Q390X mouse. Shown are normal interictal EEG activity (trace designated 1); examples of spontaneous epileptiform activity seen under basal conditions (traces designated 2 and 3); and activity captured during a generalized tonic-clonic seizure event (traces designated 4 and 5). Reproduced with permission from Kang et al., 2015. Figures have been modified for brevity, for complete details see Shen et al., 2017; and Kang et al., 2015.

Figure 6: Dravet Syndrome. (A) Interictal scalp EEG in a male patient with the GABRA1 form of Dravet Syndrome. The recording shows a bilateral spike-wave discharge in the posterior regions and generalized paroxysms in response to intermittent photic stimulation. Reproduced from Johannesen et al., 2016 - permissions pending. (B) Cortical EEG recordings from two heterozygous Gabr1 KO mice maintained on different

genetic

backgrounds.

Shown

are

bipolar

and

monopolar

recording

configurations in mice on a C57Bl/6J (left set of traces) and DBA/2J (right set of traces) backgrounds that illustrate the typical spike-wave discharge patterns seen on each

background. Reproduced with permission from Arain et al. 2012. Figures have been modified for brevity, for complete details see Johannesen et al., 2016; and Arain et al., 2012.

Figure 7: Ohtahara Syndrome. (A) Interictal EEG recordings during sleep (left panel) and awake (right panel) states showing burst-suppression in female patient with the STXBP1 form of Ohtahara syndrome at 2 months of age. Reproduced with permission from Saitsu et al., 2008. (B) Cortical EEG trace from a male heterozygous Stxbp1 KO mouse showing activity in both the sleep (top trace) and awake (middle trace) states, as well as the representative spike-wave discharges that were prevalently observed. The red trace provides an expanded view of the initial spike-wave discharge event. Reproduced with permission from Kovačević et al., 2018. Figures have been modified for brevity, for complete details see Saitsu et al., 2008; and Kovačević et al., 2018.

Figure 8: Ohtahara Syndrome. (A) Interictal scalp EEG recording in a male patient with the KCNQ2 form of Ohtahara syndrome epileptic encephalopathy. The recording shows the typical burst-suppression pattern seen in these patients. Reproduced with permission from Kojima et al., 2018. (B) Cortical EEG traces from 8 channels showing normal activity in a wildtype mouse (left panel); and a single interictal epileptiform discharge in a Kcnq2A306T/A306T mouse. (C) Trace illustrating a spontaneous generalized seizure event in a Kcnq2A306T/A306T mouse. Panels B and C reproduced with permission from Singh et al., 2008. Figures have been modified for brevity, for complete details see Kojima et al., 2018; and Singh et al., 2008.

Figure 9: Ohtahara Syndrome. (A) Scalp EEG recording showing interictal activity in a male patient with the ARX form of Ohtahara syndrome. The EEG shows paroxysmal bursts followed by background suppression. Reproduced with permission from Kato et al., 2007. (B) Cortical EEG tracing from an Arx(GCG)10+7 mouse showing a spontaneous generalized seizure event. (C) Cortical EEG trace in an Arx(GCG)10+7 mouse showing a 6 Hz spike-wave discharge event that comported with a period of behavioral arrest. Reproduced with permission from Price et al., 2009. Figures have been modified for brevity, for complete details see Kato et al., 2007; and Price et al., 2009.

Highlights:   

Common epilepsy forms observed in specific rare, monogenetic, neurodevelopmental disorder patients are highlighted Characteristics of epilepsy types and hyper-excitable networks seen in mouse models of these conditions are discussed Areas of strong and weak correlations between patient presentations mouse model phenotypes are discussed