Genetic and molecular basis of epilepsy-related cognitive dysfunction

Epilepsy & Behavior 104 (2020) 106848

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Review

Genetic and molecular basis of epilepsy-related cognitive dysfunction Lin Zhu a,1, Lu Chen a,1, Puying Xu a,1, Di Lu b, Shujuan Dai a, Lianmei Zhong a, Yanbing Han a, Mengqi Zhang c, Bo Xiao c, Lvhua Chang a,⁎,2, Qian Wu a,⁎,2 a b c

Department of Neurology, First Affiliated Hospital, Kunming Medical University, 295 Xi Chang Road, Kunming, Yunnan 650032, PR China Biomedicine Engineering Research Center, Kunming Medical University, 1168 Chun Rong West Road, Kunming, Yunnan 650500, PR China Department of Neurology, Xiangya Hospital, Central South University, 87 Xiang Ya Road, Changsha, Hunan 410008, PR China

a r t i c l e

i n f o

Article history: Received 8 October 2019 Revised 6 December 2019 Accepted 6 December 2019 Available online xxxx Keywords: Epilepsy Seizure Cognitive dysfunction Gene Molecule Pathogenesis

a b s t r a c t Epilepsy is a common neurological disease characterized by recurrent seizures. About 70 million people were affected by epilepsy or epileptic seizures. Epilepsy is a complicated complex or symptomatic syndromes induced by structural, functional, and genetic causes. Meanwhile, several comorbidities are accompanied by epileptic seizures. Cognitive dysfunction is a long-standing complication associated with epileptic seizures, which severely impairs quality of life. Although the definitive pathogenic mechanisms underlying epilepsy-related cognitive dysfunction remain unclear, accumulating evidence indicates that multiple risk factors are probably involved in the development and progression of cognitive dysfunction in patients with epilepsy. These factors include the underlying etiology, recurrent seizures or status epilepticus, structural damage that induced secondary epilepsy, genetic variants, and molecular alterations. In this review, we summarize several theories that may explain the genetic and molecular basis of epilepsy-related cognitive dysfunction. © 2019 Elsevier Inc. All rights reserved.

1. Introduction Epilepsy is a common neurological disorder, which is characterized by recurrent seizures and affects approximately 70 million people [1]. Although epilepsy is generally considered to be caused by brain disorders like traumatic brain injury [2], intracranial tumors [3], cerebrovascular disease [4], neurodegenerative disorders [5], and genetic diseases or genetically related epileptic syndromes [6], about 20% of all epilepsy

syndromes are cryptogenic with an unknown etiology, leading to great diagnostic and therapeutic challenges [7]. Moreover, epilepsy is associated with an increased risk for neuropsychological comorbidities such as cognitive deficits, emotional disturbance, and psychiatric disorders, which severely impair quality of life. Clinical evaluation and therapeutic options for these comorbidities depend on the etiology of epilepsy and the age of onset [8]. Although the definitive pathogenic mechanisms underlying epilepsy-related cognitive dysfunction remain unclear,

Abbreviations: AEDs, antiepileptic drugs; GABA, gamma-aminobutyric acid; SAVAs, saporin-conjugated antivesicular GABA transporter antibodies; GABAAR, GABAA receptor; TLE, temporal lobe epilepsy; KCC2, potassium chloride cotransporter 2; CIC-2, chloride channel 2; GABABR, GABAB receptors; GAERS, Genetic Absence Epilepsy Rat from Strasbourg; NMDAR, N-methyl-D-aspartate receptor; LTP, long-term potentiation; GABRB3, γ-aminobutyric acid receptor subunit β-3; mEPSCs, miniature excitatory postsynaptic currents; PSD-95, postsynaptic density 95; APV, 2-amino-5-phosponovaleric acid; CaMKII, calmodulin dependent protein kinase II; PSD, postsynaptic density; HIP-1, Huntingtin interacting protein 1; iGluRs, ionotropic glutamate receptors; mGlu7, metabotropic glutamate receptor 7; PICK1, protein interacting with C kinase-1; A1R, adenosine A1 receptors; GlyR, glycine receptor; Ach, acetylcholine; SE, status epilepticus; ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; NREM, nonrapid eye movement; SNP, single-nucleotide polymorphism; 5-HT, 5-hydroxytryptamine; MECP2, methyl-CpG binding protein 2; SMEI, severe myoclonic epilepsy of infancy; ATP, adenosine triphosphate; LTD, long-term depression; TCA, tricarboxylic acid; PCDH19, protocadherin 19; TGF-beta1, transforming growth factor beta-1; BDNF, brain-derived neurotrophic factor; ApoE, apolipoprotein E; CDKL5, cyclin-dependent kinase-like 5; EEF1A2, elongation factor 1-α2; KCNH5, potassium channel Kv10.2; CLCN4, chloride channel 4; SUR1, sulfonylurea receptor; TBP, TATA-binding protein; STXBP1, syntaxin binding protein 1; TESC, tescalcin; DDR2, Discoidin domain-containing receptor 2; IQ, intelligence quotient; miRNAs, microRNAs; CREB, cAMP response element-binding protein; MEF2, myocyte enhancer factor-2; TrkB, tyrosine kinase receptor B; NGF, nerve growth factor; NT-3, neurotrophin-3; NT-4, neurotrophin-4; TrkA, tyrosine kinase receptor A; TrkC, tyrosine kinase receptor C; mTOR, mammalian target of rapamycin; TSC1, tuberous sclerosis complex 1; PTEN, phosphatase and tensin homolog on chromosome 10; NF1, neurofibromin 1; mTORC1, mTOR complex 1; PRSS 12, motopsin; SEZ-6, seizure-related gene 6; SNAP-25, synaptosomal-associated protein of 25 kDa; COX-2, cyclooxygenase-2; Nrf-2, nuclear factor erythroid 2-related factor 2; VGKC, voltage-gated potassium channel; BACE-1, β-site amyloid precursor protein cleaving enzyme 1; TLR-4, toll-like receptors 4; DBN, drebrin; PPARγ, peroxisome proliferator-activated receptor gamma; LIS-1, lissencephaly; IL-6, cytokine interleukin-6; ZnTs, zinc transporters; CL, cardiolipin; β2-Gpl, β2-glycoprotein; AR, α1-adrenergic receptors; Cdk5, cyclin-dependent kinase 5. ⁎ Corresponding authors at: Department of Neurology, First Affiliated Hospital, Kunming Medical University, 295 Xi Chang Road, Kunming, Yunnan 650032, PR China. E-mail addresses: [email protected] (L. Chang), [email protected] (Q. Wu). 1 First authors Lin Zhu, Lu Chen, and Puying Xu contributed equally to the work. 2 Lvhua Chang and Qian Wu contributed equally to the work.

https://doi.org/10.1016/j.yebeh.2019.106848 1525-5050/© 2019 Elsevier Inc. All rights reserved.

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epilepsy is closely associated with cognitive alteration. Most causes of epilepsy that result in brain damage, such as, traumatic injury, structural change (focal cortical dysplasia, brain atrophy, etc.), genetic variants, molecular alterations, and some autoimmune and inflammatory encephalitis, can lead to cognitive comorbidities in epilepsy. Meanwhile, epilepsy treatments (such as antiepileptic drugs and surgery) are associated with epilepsy-related cognition and behavioral disorders. Especially, in utero exposure to some antiepileptic drugs (AEDs), such as valproate, carbamazepine, lamotrigine, and phenytoin may affect cognitive functions, such as, learning and memory in children. However, the doses and types of AEDs used in different periods of pregnancy require further study [9,10]. Moreover, recurrent seizures, chronic seizures, uncontrolled seizures, and even epileptic encephalopathies were considered intimately related to progressive cognitive decline, mental problems, and behavioral deficiencies [11,12], but these issues are still controversial and need more evidence. In summary, multiple factors result in epilepsy-related cognition comorbidities. In this review, we focused on the mainstream theories that may explain the genetic and molecular basis of epilepsy-related cognitive dysfunction and may provide new insight into the clinical treatment of this disease (Fig. 1; Table 1). 2. Neurotransmitter systems and their contributions to epilepsy and cognition 2.1. GABAergic system Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system, which binds to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic neuronal processes; GABAergic interneurons contribute to epileptic seizures and neurobehavioral abnormalities by modulating hippocampal circuit function [13]. Saporin-conjugated antivesicular GABA transporter antibodies (SAVAs), which selectively disrupt the GABAergic pathway but have no impact on glutamatergic synapses, can reduce GABA release and thus trigger network hyperexcitability. This pathophysiological process may be caused by the progressive loss

of pyramidal neurons and the granule cell dispersion in the CA1 region [13]. Several molecules participate in the pathogenesis of epilepsy and epilepsy-related cognitive impairment via the GABAergic system. In mice, offspring whose mothers were exposed to A2AR antagonists during pregnancy and prior to weaning show abnormal migration of GABAergic neurons in the hippocampus, causing enhanced neuronal network excitability and seizure susceptibility as well as the loss of GABA neurons in the hippocampus and eventually leading to cognitive dysfunctions [14]. Point mutations in the gene encoding the GABAA receptor (GABAAR) [15] are associated with many types of epilepsy including catamenial epilepsy [16,17], absence epilepsy [18–20], and temporal lobe epilepsy (TLE) [21,22]. These mutations and alterations in tonic GABAAR-mediated conductance may disrupt neuronal network function [23–25]. Therefore, therapies targeting extrasynaptic GABAARs may be potentially effective to enhance recovery of cognitive function [23]. In addition, GABAARs regulate the transmembrane distribution of chloride, and GABAergic cells mediate neuronal inhibition by promoting chloride inflow via synaptic and extrasynaptic conductance in the hippocampus [26]. Both the potassium chloride cotransporter 2 (KCC2) [27–29] and voltage-gated chloride channel 2 (CIC-2) [30,31] are associated with epilepsy, including TLE and absence seizures. The ClC-2 levels in the pyramidal cells are upregulated in CA1 in pilocarpine-treated rat models, and the increase in ClC-2 currents can be reversed by L655708, a specific antagonist targeting α5 subunitcontaining GABAARs [26]. Therefore, some have speculated that CIC-2 is involved in GABAAR-mediated neuronal inhibition and thereby plays an important role in epilepsy and cognitive dysfunctions [26]. Seizures in absence epilepsy are associated with both GABAAR and GABAB receptors (GABABR), but cognitive impairment is mainly attributed to the dysfunction of GABABR. Using the Genetic Absence Epilepsy Rat from Strasbourg (GAERS), researchers have observed that seizures are enhanced by GABAAR and GABABR agonists and blocked by GABABR antagonists. Some scholars have also noted a similar phenomenon in the AY-9944 models and transgenic GABABR models of atypical absence seizures of Lennox–Gastaut syndrome [32]. Moreover, the administration of GABABR antagonists improves cognitive performance

Fig. 1. Genes and molecules in epilepsy and cognition. The Red parts indicate that those genes or molecules might have negative effect on epilepsy-related cognitive outcomes; The Blue parts indicate that those genes or molecules might have positive effect on epilepsy-related cognitive outcomes. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

L. Zhu et al. / Epilepsy & Behavior 104 (2020) 106848

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Table 1 Molecules and genes in epilepsy-related cognitive impairment. Molecules/genes GABAAR GABABR GABAergic GABRβ-3

HIP1 Glutamatergic

mGlu7R GlyR α3 CaMKII

ACh

M1-mAChR M2 mAChR M4 mAChR nAChR

Histaminergic

H1, H2, H3, H4

Free radicals Peroxynitrite

Possible mechanism

Epilepsy/epilepsy syndromes

Point mutations, neuronal network disruption Regulates KCC2, Chloride and ClC-2 Neocortical hyperexcitability, Inhibition of NMDAR function, Impair hippocampal function Thalamocortical circuits, Heterozygous mutations, Homozygous mutations, Point mutations

Somatosensory disturbances, learning Catamenial epilepsy, absence epilepsy, TLE functions impairment, cognitive deficits Lennox–Gastaut syndrome, absence Learning and memory impairment epilepsy, atypical absence seizures Absence epilepsy, Rett syndrome, Sensory processing damage, Angelman syndrome somatosensory deficiency, impaired cognition, behavioral disorders Cognitive dysfunction, behavioral Focal and generalized epilepsies disorders Absence seizures Cognitive and emotional alteration

Defects in presynaptic function, as well as alterations in AMPA and NMDA receptor function Interact with PICK1 and reduce glutamate release of mGlu7 Exhibits an excitatory function via facilitating neurotransmitter release Thr286 phosphorylation Postsynaptic density Inhibits neuronal excitability Regulates GABAergic system Depression of excitatory postsynaptic potential (EPSP) via M4 Specific mutations (CHRNA4, CHRNB2 and CHRNA2) Modulating the homeostasis of neurotransmitter systems, such as AKT/GSK-3β, JNK and Ras-Raf-MEK Mitochondrial damage and activation of glutamate and NMDA receptors Inhibits LTP and induces GABA release Loss-of-function mutations Reduce excitatory synaptic transmission

MECP2

Cognitive outcome

TLE

Cognitive dysfunction and anxiety

TLE, Angelman syndrome, hyperthermia induced seizures TLE TLE TLE

Spatial learning and memory impairment Long-term cognitive deficits Cognitive dysfunction (animal) Cognitive dysfunction (animal) Cognitive dysfunction (animal)

ADNFLE

Executive deficits, visuospatial attention deficits, verbal memory impairment

TLE

Cognitive protection (possible)

Rett syndrome, secondary epilepsy, TLE, etc. TLE Rett syndrome, partial seizures, generalized seizures, Lennox–Gastaut syndrome, myoclonic status

Cognitive impairment Cognitive impairment Cognitive deficits Cognitive deficits Spatial memory impairment Memory dysfunction, cognitive impairment Intellectual disability Behavioral abnormalities Cognitive impairment

Truncation or exonic deletion mutations Impair sodium channel protein Nav1.1

Dravet syndrome

ATP

Modulate LTP and LTD

TLE neonatal seizures

PCDH19

Missense substitutions, premature termination (frameshift, nonsense, and splice-site mutations), in-frame deletion

Focal and generalized seizure, infantile seizures, early febrile seizures

Targets neuronal apoptosis

TLE

Cognitive, memory and behavioral protection

BDNF

Dendrite growth inhibition Neuronal Activity Neuronal and synaptic growth and differentiation

TLE, seizure disorders, Rett syndrome

Fear learning, memory and spatial cognition impairment

mTOR

Regulates TSC1, TSC2, PTEN, NF1 BDNF, etc.

Focal cortical dysplasia, infantile spasms, TLE

Cognitive, memory and behavioral protection

SCN

Bcl Family

SCN1A, SCN2B

Bcl-2, Bcl-xl, Bcl-w, Puma, Mcl-1, Bax, Bid

TLE, temporal lobe epilepsy; ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; LTP, long-term potentiation; LTD, long-term depression.

[32–34], whereas GABABR agonists impair learning and memory [35–38]. In the WAG/Rij rats, another model of absence seizure, a decrease in presynaptic GABABR function in the neocortex has been demonstrated to contribute to neocortical hyperexcitability [39]. In the lethargic models, GABABR antagonists suppress absence seizures by regulating GABABR-mediated inhibition on N-methyl-D-aspartate receptor (NMDAR) function, while GABABR agonists exhibit opposite effects [40]. In the AY-9944 models, cognitive dysfunction secondary to atypical absence seizures is GABABR-dependent. Additionally, hippocampal long-term potentiation (LTP) is reduced, leading to the impairment of hippocampal function, which is independent of seizure activities [41]. Han et al. have composed a comprehensive review concerning the correlation between GABABR function and absence epilepsy [42]. Furthermore, γ-aminobutyric acid receptor subunit β-3 (GABRB3) disruptions may be involved in the pathogenesis of epilepsy and influence cognitive outcomes. As GABRB3 is expressed in the reticular thalamic nucleus and cortex, it plays an important role in thalamocortical circuits that are essential for sensory processing. Heterozygous mutations of GABRB3 in mice have been found to cause somatosensory deficiencies [43–46] and increased epileptiform discharges [47]. Conversely, homozygous mutations are associated with absence seizures, cognitive dysfunction, disrupted coordination, and sensorimotor

deficits [47]. In human childhood absence epilepsy, point mutations in exon 1a and the N-terminal exon 2 of GABRB3 have been found to promote hyperglycosylation and reduced GABA currents. Moreover, reduced expression of GABRB3 has been observed in neurodevelopmental diseases, such as Rett syndrome, Angelman syndrome, and autism spectrum disorders [48,49]. Tanaka et al. have thoroughly discussed the relationship of GABRB3 with epilepsy and epilepsy-related cognitive outcomes [47]. 2.2. Glutamatergic system Several molecules participate in synaptic glutamatergic neurotransmission and their role in epilepsy. In chronic models induced by bicuculline, a competitive antagonist targeting the GABAAR, wholecell electrophysiological recordings on pyramidal neurons have demonstrated a reduction in the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), which is mediated by AMPA (2-amino-3-3-hydroxy-5-methyl-isoxazole-4-yl propionic acid) and NMDARs [50]. Additionally, expression levels of glutamatergic synaptic markers, such as, postsynaptic density 95 (PSD-95), are significantly decreased, indicating that seizures may induce inhibition of the growth of dendritic arbors that results in a reduced number of glutamatergic synapses on dendrites [50,51]. In the bicuculline model, administration of

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2-amino-5-phosponovaleric acid (APV; an NMDAR antagonist) can abolish seizure-induced dendritic growth suppression as well as the alteration in the expression of the glutamatergic postsynaptic proteins, suggesting that seizure-induced dendritic growth suppression in hippocampal CA1 may be NMDAR-dependent. Through NMDARs, calcium signaling affects several physiological activities, including the transcription of genes related to dendritic growth and formation of dendrites [52]. Calmodulin dependent protein kinase II (CaMKII), a Ser/Thr protein kinase containing four isoforms (α, β, γ, δ), is essential for the formation of synapses, synthesis, the secretion of neurotransmitters, the function of receptors and ion channels, synaptic plasticity, and cognition [52–56]; CaMKII is associated with various types of epilepsy. Dong and Rosenberg found that the pentylenetetrazol-induced brief seizure can result in a remarkable decline in CaMKII Thr286 phosphorylation [57]. Ni et al. observed a decrease in CaMKII mRNA levels in penicillin-induced developmental epilepticus, which may explain long-term cognitive deficits in this model [58]. Moreover, changes in the expression level of total CaMKIIα and p-T286-CaMKIIα in the postsynaptic density (PSD) and translocation of total CaMKIIα from the PSD to the cytosol were noted, which may be potential mechanisms underlying spatial learning and memory impairment in hyperthermia-induced seizures [59]. Deletion mutations in the gene encoding Huntingtin interacting protein 1 (HIP-1) are associated with clinical epilepsy, including cognitive and neurobehavioral disorders [60]. Behavioral problems linked to deletion in the HIP-1 gene include inattention, hyperactivity, impulsivity, aggression, autism, depression, and self-abuse. Animal experiments have proven that both homozygous and heterozygous deletions in the HIP-1 gene may cause epilepsy. Additionally, depletion of HIP-1 can result in presynaptic dysfunction and functional abnormalities in the ratio of AMPA and NMDAR function [61,62]; HIP-1 colocalizes with NMDA ionotropic glutamate receptors (iGluRs) in hippocampal and cortical neurons. Relevant studies have found that a loss of HIP-1 can decrease NMDA-induced AMPA-type iGluR clathrin-mediated internalization [61,63]. Additionally, HIP1 insufficiency disrupts the maintenance of surface AMPA receptors that are required for synaptic potentiation [64]. In summary, because of the role of HIP1 in AMPA and NMDA iGluR functions, depletion of HIP1 can predispose the brain to epilepsy and relative cognitive disturbances. Metabotropic glutamate receptor 7 (mGlu7) receptors are members of the group-III metabotropic glutamate receptors [65,66]. Sansig et al. have found that reduction in mGlu7 receptors increases the risk of convulsive seizures [67]. Moreover, the interaction between mGlu7 receptors and protein interacting with C kinase-1 (PICK1) can cause absence seizures [68,69]. The mGlu7 receptors are located in the presynaptic area and reduce glutamate release of mGlu7 by acting with GABABR, adenosine A1 receptors (A1R), and N-type voltage-sensitive calcium channels in cortical synaptosomes [70]. Based on this evidence, mGlu7 receptors are considered an important target for cognitive and emotional functions. Changes in the glycine receptor (GlyR) α3 subunit are associated with the pathophysiology of epilepsy [71–73]. In patients with TLE, a P185L amino acid transition can elevate the expression of GlyR α3, resulting in the hyperactivity of neurotransmitter receptors. Activation of the presynaptic GlyR α3 L185L transition can promote the release of neurotransmitters, enhancing neuronal functions in the cortical network. Thus, GlyR variations can disrupt homeostatic maintenance of neural excitability and trigger neuropsychiatric disorders, such as, cognitive decline and anxiety [74]. 2.3. Acetylcholinergic system Acetylcholine (ACh) is a neurotransmitter involved both in cognitive processes [75] and in seizure generation [76–78]. A study on rat models of status epilepticus (SE) showed that a single and sustained generalized seizure can increase responsiveness to cholinergic stimuli [79,80].

The M1 mAChR, a metabotropic ACh receptor, colocalizes with NR1, a subunit of the NMDAR [81], and plays an important role in the development of epilepsy. Pilocarpine cannot trigger seizures in mouse models lacking M1 mAChR [82]. Additionally, the M1 mAChR is associated with the Kv7 channel-mediated M-current that inhibits neuronal excitability [83]. The M2 mAChR also participates in the development of epilepsy through a decrease in the release of GABA [84]. Under normal physiological conditions, ACh transiently inhibits GABA release and activates the M2 mAChR, facilitating the expression of LTP [85]. However, in patients with TLE, GABAergic transmission affects mAChR-mediated regulation of LTP and impairs the M2 mAChR-mediated regulation of the GABAergic system [84]. Suppression of cholinergic signaling also causes cognitive impairment in mice [86] as well as schizophrenia and Alzheimer's disease in humans [87,88]. Some scholars have proposed that mAChRs can regulate cognitive function by increasing neuronal activity via the M1 mAChR, suppressing the excitatory postsynaptic potential via M4 mAChR, and suppressing the generation of inhibitory postsynaptic potentials via M2 mAChR [84,89]. These findings highlight the complex role of muscarinic receptors in the pathogenesis of epilepsy and relevant cognitive dysfunction [84]. Alteration in one neurotransmitter system may affect the activity of other systems through synergistic actions or cross-activation. Both NMDARs and endogenous ACh participate in modulating interictal electrical discharges in vitro. Mikroulis and Psarropoulou found that mAChR positively contributes to the frequency of NMDAR-dependent epileptiform discharges, which is associated with an increased level of endogenous ACh. Additionally, the mAChRmediated increase in the frequency of interictal electrical discharges is more remarkable following early-life generalized sustained convulsion [75]. The hyperactivity of the cholinergic system in the hippocampus may impair cognitive function and may also lower the seizure threshold in adults [75]. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an inherited epilepsy syndrome. Several mutations in nicotinic receptor subunit genes have been identified [90,91]. These nucleotide variants can cause a special form of epilepsy manifesting as nocturnal seizures that occur mostly during nonrapid eye movement (NREM) sleep [92]. This inherited disease was first reported by Scheffer et al. in a family of 27 affected individuals in which there were no neuropsychiatric or cognitive symptoms [93]. However, recent studies have demonstrated that cognitive disorders, especially deficits in executive functions, are common in patients with ADNFLE [94]. Currently, the relationship between ADNFLE and cognitive impairment remains unknown. Interestingly, several mutations in the AchRs subunit genes CHRNA4, CHRNB2, and CHRNA2 have been reported in families with ADNFLE [95]. Moreover, Bertrand et al. discovered a mutation in the β2 nAChR in a pair of monozygotic twins who exhibited verbal memory disabilities [96]. Subsequently, Picard et al. identified three mutations in the CHRNA4 gene and one mutation in the CHRNB2 gene in 11 patients who presented with memory decline and executive dysfunction [94]. The CHRNA4 and CHRNB2 genes encode nAchR subunits, and an increasing number of studies showed that genetic variants of these subunits may be associated with different cognitive dysfunctions. For example, the single-nucleotide polymorphism (SNP) C1545T in the CHRNA4 gene is associated with visuospatial attention deficits [97,98], and mutations in the α4 subunit, including S252L, T265I, and S248F, may affect core executive functions [94,99]. Mutations in β2 nAChR may affect general intellectual skills and verbal functions [96], and the missense mutation I312M in the CHRNB2 gene is associated with cognitive impairments, especially verbal memory deficiencies [96,100]. Steinlein et al. noted that the nAChR mutation-related risk for cognitive disorders was lower than the ADNFLE mutation-related risk [92]. In summary, genetic variants in nicotinic receptors may lead to alterations in the cholinergic transmission system, which is associated with psychiatric and behavioral

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symptoms [101–105], and the relationship between ADNFLE mutations and neuropsychiatric impairments deserves more attention [92]. 2.4. Histaminergic system The central histaminergic system is controlled by H1, H2, H3, and H4 receptors and is also involved in the pathogenesis of epilepsy. The histaminergic system modulates the homeostasis of neurotransmitter systems via H3 heteroreceptors, which regulate the secretion of neurotransmitters such as GABA, glutamate, dopamine, 5hydroxytryptamine (5-HT), noradrenaline, and acetylcholine [106]. Therefore, the histaminergic system is essential for homeostatic maintenance and cognitive function [104,106]. Some scholars have found that the overproduction of histamine can inhibit seizures, indicating that histamine has neuroprotective effects [107–109]. Additionally, histamine can protect hippocampal neurons from kainate-induced injury through H1 and H3 receptors [110]. Further studies have suggested that this protective effect may be mediated by AKT/GSK-3β [111], JNK, and Ras-RafMEK [109,112] signaling pathways and heat shock proteins [113]. Bhowmik et al. have performed a comprehensive review describing the relationship between histamine H3 receptor and epilepsy as well as epilepsy-related cognitive dysfunctions [108]. 3. Genetic epilepsy syndromes and cognition 3.1. Rett syndrome Rett syndrome is to a neurodevelopmental disease characterized by progressive motor deficits, cognitive dysfunction, social-behavioral problems, and seizures [114]. Approximately 70%~80% of all patients with Rett syndrome exhibit seizures at 2~5 years of age [115–118]. Epilepsy forms in the Rett syndrome include partial seizures, generalized seizures [117–119], Lennox–Gastaut syndrome, and myoclonic status [120]. Accumulating evidence shows that loss-of-function mutations in the gene encoding X-linked methyl-CpG binding protein 2 (MECP2) can cause Rett syndrome [121] in humans [122] and animal models [123–126]; MECP2 dysfunction results in a reduction of excitatory synaptic transmission in the hippocampus [125,127], impairment of LTP at excitatory synapses in the hippocampus [128–130], alterations in inhibitory transmission in the whole brain [131–133], and hyperexcitability in cortical neurons and networks [134–136]. These changes may be one plausible explanation for seizures and cognitive disabilities. Recent studies have found that knockout of MECP2 in excitatory neurons inhibits GABAergic transmission in pyramidal neurons in the somatosensory cortex [114]. Moreover, loss of MECP2 in excitatory neurons may reduce the number of GABAergic synapses and increase the excitability of pyramidal neurons [114]. Considering that MECP2 is important for maintaining GABAergic transmission and cortical circuits, we speculate that MECP2 dysfunction is a crucial contributor to cognitive deficits in patients with Rett syndrome. 3.2. Dravet syndrome Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI) [137], is a rare form of epilepsy that manifests as seizures, developmental retardation, and cognitive dysfunction [138,139]. Dravet syndrome is caused by truncation or exonic deletion mutations in the SCN1A [140], SCN2A [141], and GABRG2 genes [142]. The exact mechanisms underlying epilepsy and cognitive disorders caused by GABRG2 mutations remain unclear; nevertheless, truncation of GABRG2 and its subunits may lead to the formation of protein aggregates, which is a pathological hallmark of neurodegenerative diseases [138]. The SCN1A gene variants include missense mutations, truncating mutations that generate a truncated protein [143], and genomic deletions and duplications [144]. The SCN1A mutations have been found

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to be associated with both seizures and cognitive impairment in Dravet syndrome [145]. Some scholars have identified SCN1A mutations that impair the function of the sodium channel protein Nav1.1, leading to a decrease in sodium currents [146], and they may cause an outburst of action potentials in inhibitory interneurons [147]. In addition, SCN1A mutations can disrupt the overall excitation–inhibition balance and thus cause abnormal activation of hippocampal circuits, which lower the threshold for seizures [148]. N6-cyclopentyladenosine, an A1R agonist, can reduce presynaptic depolarization through the activation of delayed rectifying potassium channels and blocking voltage-gated calcium channels [149] producing the inhibition of aberrant neural circuit hyperexcitability in experimental Dravet syndrome models and reducing febrile seizure-like events without blocking excitatory synaptic transmission [148]. These results indicate that A1R may be involved in hippocampal circuits in Dravet syndrome by reducing excitability through a mechanism that differs from traditional agents that boost GABA [150]. In short, presynaptic or postsynaptic hyperexcitation and abnormal regulation of hippocampal circuits may be the mechanisms underlying early-life febrile seizures and cognitive impairment in Dravet syndrome [148]. Although cognitive disorders are common in pediatric patients with Dravet syndrome, antiepileptic therapies do not improve cognitive function [151]. Therefore, brain abnormalities in Dravet syndrome may contribute to cognitive dysfunction through mechanisms independent of epilepsy [151]. Some have hypothesized that impaired function of Nav1.1 may be a potential mechanism, which is also associated with autism [152,153] and Alzheimer's disease [154–157]. Nav1.1 dysfunction disrupts neural network function [158]. The selective knockdown of Nav1.1 in the Broca area results in spatial memory impairment through the dysregulation of hippocampal theta frequency [151]. 4. Oxidative stress 4.1. Free radicals Epileptic seizures and postictal periods are characterized by increased energy turnover in the brain and massive energy consumption [159]. These alterations lead to oxidative stress and the overproduction of free radicals, such as, hydroxyl and nitroxyl [160]. The generation of free radicals is mediated by two mechanisms: mitochondrial damage [160,161] and the activation of glutamate and NMDARs [162]. Mitochondrial damage is associated with several genetic forms of epilepsy [163,164]. Free radicals may aggravate epilepsy and cognitive dysfunction by directly influencing LTP [165,166], and the free-radical levels are correlated with epilepsy severity [167]. Additionally, pretreatment with melatonin (N-acetyl-5-methoxytrptamine), an indoleamine derivative of serotonin with potent antioxidant and free-radical scavenger properties [168], can reduce the level of hydroxyl and prevent cognitive impairment in rat models [159,169]. Another free-radical scavenger, Trolox, exhibits neuroprotective effects against epilepsy and cognitive dysfunction in a mouse model of Rett syndrome [170]. However, although there is evidence linking free radicals to epilepsy-related cognitive impairment, the exact mechanism underlying this association remains to be fully elucidated. 4.2. Peroxynitrite Peroxynitrite is a strong oxidant and cytotoxic mediator produced from the reaction of nitric oxide and the superoxide radical, which is the major contributor to seizures and hypoxic–ischemic brain damage [171–173]. Peroxynitrite can cause cognitive deficits by inhibiting LTP and inducing GABA release in the hippocampus [174]. Thus, we speculate that peroxynitrite may contribute to epileptic seizures and epilepsy-related cognitive dysfunctions through GABA signaling [175].

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4.3. Adenosine triphosphate (ATP) Abnormal adenosine triphosphate (ATP) levels can lead to seizures and epilepsy-related cognitive impairment through energy failure and impairing LTP and long-term depression (LTD). The ATP levels reflect cell energy levels and are regulated by the tricarboxylic acid (TCA) cycle. Deficits of the TCA cycle can lead to seizures, and its supplementation can reverse seizures and seizure-induced cell death [176]. Both LTP and LTD are regulated by ATP and its dephosphorylated product adenosine [177]. In rat models, ATP hydrolysis is enhanced by kainate during the neonatal period, which is important for LTP induction. Cognato et al. hypothesized that enhanced ATP hydrolysis regulates cognitive impairment in adult rats that experienced a convulsive seizure during the postnatal period [177]. The correlation between purinergic metabolism and cognitive dysfunction following neonatal seizures may improve our understanding of seizure-induced memory deficits [177].

In patients with epilepsy, Bcl-2 levels are elevated in serum and brain tissues [192,206], and its high level is as a hallmark of activated apoptosis signaling in pediatric TLE [206]. Additionally, the serum Bcl2 levels are correlated with the clinical characteristics of epilepsy, such as, the disease duration, seizure frequency, intellectual ability, and disease severity [206]. Clusterin, a protein interacting with Bcl-xL, has proapoptotic effects and causes hippocampal neuronal death in CA3 in patients who experienced seizures [207]. Transforming growth factor beta-1 (TGF-beta1) has neuroprotective properties, which can protect neurons against seizure-induced damage and improve cognitive function [208]. In lithium-pilocarpine-induced status epilepticus rats, exogenous TGF-beta1 administration significantly attenuates the detrimental effects of hippocampal injury, which is mediated by the upregulation of Bcl-2 and downregulated Bax and caspase-3 [208]. Therapeutic strategies targeting apoptosis hold promise for treating seizureinduced brain damage and cognitive disorders. 6. Other molecules

5. Genes and epigenetics 5.1. Protocadherin Protocadherin 19 (PCDH19) is a major epileptogenic gene, and its mutations are associated with cognitive impairment induced by epilepsy [178,179]; PCDH19 may participate in the pathogenesis of focal and generalized seizures and infantile or early-onset febrile seizures [169,180]. Patients with PCDH19 mutations usually exhibit intellectual disabilities, and more than half of them present behavioral abnormalities [181] and cognitive impairment [169]. Clinical variations in the PCDH19 gene include missense substitutions, truncating mutations, and fragment deletions [169,180]. Until recently, the specific relationship between genotypes and phenotypes is still unclear [169]. Camacho et al. found that PCDH19 mutations have a female predominance, and PCDH19-related seizures tend to diminish or even disappear in adolescence. The authors also noted that mental disability and psychiatric symptoms are more severe in these patients [181]. Furthermore, Marini et al. demonstrated that patients carrying PCDH19 mutations usually have focal seizures accompanied by affective symptoms, indicating that the frontotemporal limbic system may be involved in PCDH19related epilepsy [169]. 5.2. Bcl gene family Neuronal loss may disrupt the excitation–inhibition balance within brain networks [182,183], and it can lead to epilepsy by affecting the minimal latency [184,185], minimal delayed spontaneous seizures, [186] or by disrupting the thalamocortical circuits [187]. Neuroprotective treatment targeting neuronal apoptosis can reduce epilepsy risk [188], reduce the number of spontaneous seizures [189], and improve memory and behavioral abnormalities [190]. Seizure-induced neuronal death is characterized by excitotoxic necrosis and the activation of apoptosis signal pathways. Bcl family proteins, such as Bcl-2, Bcl-xL, Puma, Bcl-w, and Mcl-1, are crucial molecules regulating the initiation, integration, and execution of the intrinsic apoptosis pathway [191–194]. Intrinsic apoptosis is initiated by DNA damage, hypoxia, calcium overload, growth factor withdrawal, oxidative stress, and misfolded proteins [195,196]. Seizures can downregulate the expression of antiapoptotic genes, such as, Bcl-2 [197], Bcl-w [198,199], and Mcl-1 [200], and upregulate the expression of proapoptotic genes, such as, Bax [201–203], Bid [137], Bad [202], Bim [204], Puma [137], and Bmf [203]. Relevant evidence showed that downregulation of proapoptotic genes, such as, Puma, Bak, and Bmf, can protect against seizure-induced neuronal death. Conversely, downregulated of antiapoptotic Mcl-1 and Bcl-w leads to neuronal injury in the hippocampus [205].

6.1. BDNF Brain-derived neurotrophic factor (BDNF), a 14-kDa secreted protein, is involved in neuronal activity, neuronal and synaptic growth and differentiation, and the growth of pyramidal cell dendrites [209,210]. The expression of BDNF is altered in epileptic animal models and in patients with TLE [211]. Vezzani et al. found that seizures can elevate the expression of BDNF mRNA and protein [212]. Additional evidence indicates that loss of BDNF can suppress hyperexcitability [213], and that BDNF administration within the hippocampus induces the epileptogenesis [214]. Furthermore, aberrant epigenetic regulation of BDNF plays an important role in the pathophysiology of seizureinduced cognitive deficiencies, Rett syndrome, Alzheimer's disease, and schizophrenia [209]. Transcription of BDNF is modulated by various transcription factors, such as, MECP2, myocyte enhancer factor-2 (MEF2), and cAMP response element-binding protein (CREB) [215], which may be involved in seizure-induced dendrite growth inhibition [216]. Brain-derived neurotrophic factor participates in the dynamic transcriptional mechanisms involved in cognition in the adult brain. In addition, BDNF can promote tyrosine phosphorylation in the cytoplasm by binding to tyrosine kinase receptor B (TrkB), which is a vital process for the activation of intracellular signaling cascades [217]. Brain-derived neurotrophic factor has three analogs, nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), while TrkB has two analogs, tyrosine kinase receptor A (TrkA) and tyrosine kinase receptor C (TrkC). NGF binds to TrkA, BDNF and NT4 to TrkB, and NT3 to TrkC. In animal models and humans with epilepsy, seizures induce a striking increase in BDNF expression [218–221] and enhance the activation of TrkB in dentate granule cells and mossy fiber pathways in the hippocampus [222]. Additionally, BDNF enhances LTP [223] and synaptic plasticity in epileptic animal models [224]. Similarly, activation of TrkB in mossy fiber pathways can enhance LTP in the hippocampus in the kainic acid-induced epilepsy models [225]. Furthermore, activation of TrkB mediated by BDNF can compromise GABA-mediated inhibition [226]. Increasing the level of BDNF or TrkB via exogenous injection or transgenic techniques exacerbates seizure susceptibility and severity [227]. Conversely, the conditional knockout of TrkB prevents epilepsy progression, and the deletion of TrkB also reduces the risk for epilepsy in animal models [217]. Noteworthy, estrogen can elevate BDNF levels; hippocampal neurons and estrogen administration in female rats produce epileptiform responses of CA3 pyramidal cells, which are reversed by a Trk antagonist [228]. These findings strongly suggest that BDNF and Trk signaling may contribute to epileptogenesis [217,229]. Several studies have reported an association between BDNF and fear learning or spatial cognition [230–232]. The fear stimulus may elevate BDNF transcript including exons I and IV in the amygdala [233],

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hippocampus, and prefrontal lobe cortex [230]. This process is regulated by chromatin modification, which is characterized by increased histone acetylation (prominently histone H4) and phosphorylation at the respective promoters [234]. Upregulated histone H4 acetylation at BDNF gene promoters is observed in the hippocampus in rat models of status epilepticus [235]. Tian et al. also noted that the BDNF transcription during long-term memory formation is mediated by NMDA glutamate receptor activation [236]. Despite this cumulative evidence, the role of BDNF in the development of epilepsy and related cognitive impairment requires further investigation. 6.2. Mammalian target of rapamycin (mTOR) In the brain, mammalian target of rapamycin (mTOR) is a kinase modulated by glutamate and dopamine receptors [237], and it is negatively regulated by tumor suppressor genes tuberous sclerosis complex 1 (TSC1), TSC2, phosphatase and tensin homolog on chromosome 10 (PTEN), and neurofibromin 1 (NF1) [20]. Dysregulation of mTOR may lead to “TORopathies” [238], a disease spectrum including focal cortical dysplasia, hemimegalencephaly, tuberous sclerosis, infantile spasms, and TLE [239]. In the infantile spasm model, rapamycin treatment effectively inhibits the overactivation of the mTOR signaling in the cortex, which suppresses spasms and partially improves cognitive deficits [239]. In epilepsy models, rapamycin ameliorates the epilepsy-related pathology and reduced the frequency of spontaneous seizures [240]. Further investigations showed that the protective effects of mTOR inhibitors are time- and dose-dependent [241]. In rats with acute hypoxia-induced neonatal seizures, seizures would activate mTOR complex 1 (mTORC1) and its downstream targets, such as, phospho-4E-BP1 (Thr37/46), phospho-p70S6K (Thr389), and phospho-S6 (Ser235/236). Upstream signaling molecules, including BDNF, phospho-Akt (Thr308), and phospho-ERK (Thr202/Tyr204), may also be activated [242]. Additionally, rapamycin, the specific mTORC1 inhibitor, can reverse the increased glutamatergic neurotransmission and seizure susceptibility, and it can attenuate epileptic seizures and neuropsychic disturbances [242]. Therefore, the mTORC1 signaling pathway may be a promising target for the treatment of seizures and related cognitive disorders [242]. The PTEN and mTOR coregulate the process of epileptogenesis and cognitive functions; PTEN negatively regulates the activity of the PI3K/ Akt/mTOR pathway, a signaling cascade critical to cell proliferation Table 2 Other genes and molecules possibly related to epilepsy and cognition with unclear mechanisms. Type

Other genes

Other molecules

SNP variants MicroRNAs

Identified molecules Histone demethylase KDM5C (JARID1C/SMCX) [244]; Cyclin-dependent kinase-like 5 (CDKL5); Elongation factor 1-α2 (EEF1A2); Voltage-gated potassium channel Kv10.2 (KCNH5); Chloride channel 4 (CLCN4); ARHGEF15 (an EC-specific guanine nucleotide exchange factor) [245]; Sulfonylurea receptor (SUR1) (Hernandez-Sanchez et al., 2001); TATA-binding protein (TBP) [246]; Syntaxin binding protein 1 (STXBP1) [247] Apolipoprotein E (ApoE) [248]; Motopsin (PRSS 12) [249]; seizure-related gene 6 (SEZ-6) [249]; Synaptosomal-associated protein of 25 kDa (SNAP-25) [250]; Cyclooxygenase-2 (COX-2) [251]; Nuclear factor erythroid 2-related factor 2 (Nrf-2) [252]; Voltage-gated potassium channel (VGKC) [253]; β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) [254]; Toll-like receptors 4 (TLR-4) [255]; Drebrin (DBN) [256]; Kainite [257]; Peroxisome proliferator-activated receptor gamma (PPARγ) [258]; Lissencephaly (LIS-1) [259]; Cytokine interleukin-6 (IL-6) [260]; Autophagy and zinc transporters (ZnTs) [261]; Cardiolipin (CL) and β2-glycoprotein (β2-Gpl) antibodies [262]; α1-adrenergic receptors (AR) subtypes [263]; Cyclin-dependent kinase 5 (Cdk5); SnoNs (an embryonically regulated transcription factor) rs7294919 [264]; rs10784502 [265]; rs10494373 [266] miR-34a, miR-132, miR-184, miR-21, miR-29a, miR-34a, miR-125b, and miR-497 [267–270]

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and cell growth. Also, mutations in the PTEN increase the risk for epilepsy and autism [243]. Consistent with this idea, loss of PTEN leads to seizures and cognitive dysfunctions in mice [243]. These findings indicate that PTEN is an essential molecule for neuronal development and excitability in the cerebral cortex [243]. 6.3. More genes, molecules, microRNA, and SNP variants Several other genes, molecules, miRNA, and SNP variants showed in Table 2 have been shown to be associated with different types of epileptic seizures and epilepsy-related cognitive deficiencies. Although the exact mechanisms remain unclear, we hypothesize that a complex molecular and genetic network is involved in epileptogenesis, and that the molecules and genes in this network are potential targets for improving the clinical prognosis of epilepsy and cognitive outcomes. 7. Conclusions There are a variety of molecules and pathways involved in the pathogenesis of epilepsy and related cognitive deficits. We hope that this review provides readers, researchers, and clinicians an overall perspective on the genetic and molecular factors that are possibly associated with seizure-induced cognitive decline. Acknowledgments None. Funding This work was supported by the National Natural Science Foundation of China (81601134, 81501025), Yunnan Applied Basic Research Projects (2017FE468(-144)), the Natural Science Foundation of Hunan Province (No. 2016JJ3174), Yunnan Provincial Key Projects (2017FA041), Program for Science and Technology Innovation Team in Kunming Medical University (CXTD201614) and funded by China Scholarship Council. Declaration of competing interest None. Rereferences [1] Thijs RD, Surges R, O'Brien TJ, Sander JW. Epilepsy in adults. Lancet 2019;393: 689–701. [2] Gazaryan LM, Selyanina NV, Karakulova YV, Sosnin DY. The level of neuregulin-1 after traumatic brain injury and formation of post-traumatic epilepsy. Bull Exp Biol Med 2019;167:207–9. [3] Robert-Boire V, Desnous B, Lortie A, Carmant L, Ellezam B, Weil AG, et al. Seizures in pediatric patients with primary brain tumors. Pediatr Neurol 2019;97:50–5. [4] Yang C, Nicholas VH, Zhao J, Wu B, Zhong H, Li Y, et al. A novel CCM1/KRIT1 heterozygous nonsense mutation (c.1864CNT) associated with familial cerebral cavernous malformation: a genetic insight from an 8-year continuous observational study. J Mol Neurosci 2017;61:511–23. [5] Lehmann-Horn F, D'Amico A, Bertini E, Lomonaco M, Merlini L, Nelson KR, et al. Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life. Acta Myol 2017;36:125–34. [6] Symonds JD, Zuberi SM, Johnson MR. Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment. Curr Opin Neurol 2017;30:193–9. [7] Stommel EW, Seguin R, Thadani VM, Schwartzman JD, Gilbert K, Ryan KA, et al. Cryptogenic epilepsy: an infectious etiology? Epilepsia 2001;42:436–8. [8] Devinsky O, Vezzani A, O'Brien TJ, Jette N, Scheffer IE, de Curtis M, et al. Epilepsy. Nat Rev Dis Primers 2018;4:18024. [9] Cohen MJ, Meador KJ, May R, Loblein H, Conrad T, Baker GA, et al. Fetal antiepileptic drug exposure and learning and memory functioning at 6years of age: the NEAD prospective observational study. Epilepsy Behav 2019;92:154–64. [10] McCorry D, Bromley R. Does in utero exposure of antiepileptic drugs lead to failure to reach full cognitive potential? Seizure 2015;28:51–6. [11] Spatola M, Dalmau J. Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis. Curr Opin Neurol 2017;30:345–53. [12] Helmstaedter C, Witt JA. Epilepsy and cognition — a bidirectional relationship? Seizure 2017;49:83–9.

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