Identification of KCC2 Mutations in Human Epilepsy Suggests Strategies for Therapeutic Transporter Modulation

Abstract

Epilepsy is a common neurological disorder characterized by recurrent and unprovoked seizures thought to arise from impaired balance between neuronal excitation and inhibition. Our understanding of the neurophysiological mechanisms that render the brain epileptogenic remains incomplete, reflected by the lack of satisfactory treatments that can effectively prevent epileptic seizures without significant drug-related adverse effects. Type 2 K+-Cl− cotransporter (KCC2), encoded by SLC12A5, is important for chloride homeostasis and neuronal excitability. KCC2 dysfunction attenuates Cl− extrusion and impairs GABAergic inhibition, and can lead to neuronal hyperexcitability. Converging lines of evidence from human genetics have secured the link between KCC2 dysfunction and the development of epilepsy. Here, we review KCC2 mutations in human epilepsy and discuss potential therapeutic strategies based on the functional impact of these mutations. We suggest that a strategy of augmenting KCC2 activity by antagonizing its critical inhibitory phosphorylation sites may be a particularly efficacious method of facilitating Cl− extrusion and restoring GABA inhibition to treat medication-refractory epilepsy and other seizure disorders.

TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice

“…Further, AAV-Cre-mediated reduction of KCC2 in the CA1 and dentate gyrus of the adult mouse hippocampus resulted in some of the core phenotypes of medial temporal lobe epilepsy, such as spontaneous seizures, gliosis, and neuronal loss (55). These results from adult mouse models of epilepsy, with the prevalence of pathogenic KCC2 mutations in human epilepsy (56), support the critical role of KCC2 and pathways that promote its hypofunction in epilepsy.…”

Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model

“…KCC2 expression and function increase during development, resulting in a lower [Cl -]i that coincides with a developmental shift from depolarizing to hyperpolarizing GABAergic signaling. The importance of KCC2 function in seizure susceptibility is supported by emerging evidence from human genetics, as pathogenic variants in SLC12A5 are associated with the development of idiopathic generalized epilepsy and early infantile epileptic encephalopathy (OMIM #616685 and #616645, respectively) (9).…”

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

“…Further, AAV- Cre mediated reduction of KCC2 in the CA1 and dentate gyrus of the adult mouse hippocampus resulted in some of the core phenotypes of medial temporal lobe epilepsy, such as spontaneous seizures, gliosis, and neuronal loss ( 56 ). These results from adult mouse models of epilepsy, and the prevalence of pathogenic KCC2 mutations in human epilepsy ( 57 ) support the critical role of KCC2 and pathways that promote its hypofunction in epilepsy.…”