CNTNAP4 Impacts Epilepsy Through GABA A Receptors Regulation: Evidence From Temporal Lobe Epilepsy Patients and Mouse Models

Abstract

Epilepsy is a serious neurological condition characterized by recurrent unprovoked seizures. The exact etiology of epilepsy is not fully understood. Here, we demonstrated that the expression of contactin-associated protein-like 4 (CNTNAP4) was decreased in the temporal neocortex of epileptic patients and in the hippocampus and cortex of epileptic mice. Lentivirus-mediated knock-down of CNTNAP4 in the hippocampus increased mice susceptibility to epilepsy. Conversely, lentivirus-mediated overexpression of CNTNAP4 decreased epileptic behavior in mice. CNTNAP4 affected neuronal excitability and inhibitory synaptic transmission via postsynaptic receptors in Mg²⁺-free epilepsy cell model. Down-regulation or overexpression of CNTNAP4 in the hippocampus influenced the expression of gamma-aminobutyric acid A receptor β2/3 (GABA_ARβ2/3) membrane protein, without affecting total GABA_ARβ2/3 protein concentration in epileptic mice. Protein interactions between CNTNAP4, GABA_ARβ2/3 and gamma-aminobutyric acid receptor-associated protein (GABARAP) were observed in the hippocampus of epileptic mice. These findings suggest CNTNAP4 may be involved in the occurrence and development of epilepsy through the regulation of GABA_AR function, and may be a promising target for the development of epilepsy treatment.

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