The Cytoskeleton in Epilepsy: Cause, Consequence or Bystander?
Epilepsy is a chronic condition whose hallmark feature is the occurrence of spontaneous recurrent seizures (SRS), and is typically associated with comorbid conditions, including learning and memory deficits, anxiety and depression. Epilepsy affects over 200,000 Canadians and over 15,000 new cases are diagnosed annually. Unfortunately, the mechanisms underlying epileptogenesis continue to elude us.
Insights into epileptogenesis – the molecular and cellular processes that evolve into a chronic state of SRS – have emerged from human studies, genetic rodent models of epilepsy and animal models induced by status epilepticus. Factors such as excitotoxic cell death, inflammation, extracellular matrix reorganization, astrogliosis, mossy fiber sprouting and alterations in dendritic plasticity have been proposed as relevant mechanisms for epileptogenesis. From a basic cellular point of view, all these changes are linked directly or indirectly to alterations in the cytoskeleton, the intracellular filamentous network composed of microtubules (MTs), intermediate filaments, actin filaments and their associated proteins that provide structural integrity and functionality to cells.
Unequivocal evidence for a prenatal role of the cytoskeleton in the pathogenesis of epilepsy is established in the pediatric epilepsy population. Many infants and children with severe intractable epileptic syndromes exhibit prenatal defects in cytoskeletal structure/function that cause brain malformations and neuronal migration disorders. These include double cortex syndrome and lissencephaly caused by mutations in MT-associated proteins (MAPs) Dcx and Lis1, respectively. Studies in genetic rodent models harboring deficiencies in these MAPs have enhanced our understanding of how prenatal abnormalities in the cytoskeleton lead to epilepsy via misplacement of early-born neurons and altered neuronal connectivity during brain development. In contrast, the postnatal contribution of the cytoskeleton in adult epilepsy remains elusive and controversial. Cytoskeletal disruption in the adult epileptic brain is often seen as a consequence of aberrant neuronal activity and/or death, or is considered an epiphenomenon unrelated to epileptogenesis. Importantly, our recent study using mice deficient for the cytoskeletal protein Ndel1 in postnatal forebrain excitatory neurons suggests that loss of cytoskeletal function and structure can cause epilepsy (Kiroski et al., Cereb Cortex, 2020, cover of the September issue). Indeed, the mutant mice displayed several behaviors consistent with epileptic seizures and attributes defined by the standard Racine scale. Furthermore, they exhibit electrographic and behavioral seizures, as demonstrated by video-electroencephalogram recordings using both in-depth/intra-hippocampal and surface electrodes (Kiroski et al., Cereb Cortex, 2020, cover of the September issue). Ultimately, these mice die prematurely from seizures.
For an updated review on the roles of the cytoskeleton in adult epilepsy, please consult our article entitled 'Postnatal role of the cytoskeleton in adult epileptogenesis" published in Cerebral Cortex Communications as Feature Article (Gavrilovici et al., Cereb Cortex Comm, 2020).