Defects at the crossroads of GABAergic signaling in generalized genetic epilepsies

Abstract

Seizure disorders are very common and affect 3% of the general population. The recurrent unprovoked seizures that are also called epilepsies are highly diverse as to both underlying genetic basis and clinic presentations. Recent genetic advances and sequencing technologies indicate that many epilepsies previously thought to be without known causes, or idiopathic generalized epilepsies (IGEs), are virtually genetic epilepsy as they are caused by genetic variations. IGEs are estimated to account for ~15-20% of all epilepsies. Initially IGEs were primarily considered channelopathies, because the first genetic defects identified in IGEs involved ion channel genes. However, new findings indicate that mutations in many non ion channel genes are also involved in addition to those in ion channel genes. Interestingly, mutations in many genes associated with epilepsy affect GABAergic signaling, a major biological pathway in epilepsy. Additionally, many antiepileptic drugs work via enhancing GABAergic signaling. Hence, the review will focus on the mutations that impair GABAergic signaling and selectively discuss the newly identified STXBP1, PRRT2, and DNM1 in addition to those long-established epilepsy ion channel genes that also impair GABAergic signaling like SCN1A and GABAA receptor subunit genes. GABAergic signaling includes the pre- and post- synaptic mechanisms. Some mutations, such as STXBP1, PRRT2, DNM1, and SCN1A, impair GABAergic signaling mainly via pre-synaptic mechanisms while those mutations in GABAA receptor subunit genes impair GABAergic signaling via post-synaptic mechanisms. Nevertheless, these findings suggest impaired GABAergic signaling is a converging pathway of defects for many ion channel or non ion channel mutations associated with genetic epilepsies.

A PRRT2 variant in a Chinese family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures results in loss of interaction with STX1B

“…Emerging research has demonstrated that PRRT2‐related diseases are attributable to synaptopathies . PRRT2 was found to play a key role in presynaptic vesicle secretion, especially for synchronous neurotransmitter release .…”

“…Emerging research has demonstrated that PRRT2-related diseases are attributable to synaptopathies. 31,32 PRRT2 was found to play a key role in presynaptic vesicle secretion, especially for synchronous neurotransmitter release. 16 Many genes encoding synaptic proteins, such as STXBP1, 33 SNAP25, 34 and STX1B, 20 have been linked to paroxysmal disorders.…”

Neurovascular Unit as a Source of Ischemic Stroke Biomarkers—Limitations of Experimental Studies and Perspectives for Clinical Application

“…Considering the widespread distribution of GABA in cerebral structures, in particular, in areas related to motor function, such as frontal cortex or basal ganglia (e.g., striatum, globus pallidus, subthalamic nucleus and substantia nigra), it can be expected that dysregulation of GABA-ergic neurotransmission, resulting from ischemia, may be responsible for enhancing of disorders, such as paresis, muscular tone dysregulation, or involuntary movements [61]. It can be also responsible for initiation of the epileptic activity [62]. Other brain areas in which GABA-ergic transmission disorders can bring about characteristic dysfunctions are limbic structures, such as hippocampus, amygdala, or prefrontal cortex.…”

Aberrant expression of S-SCAM causes the loss of GABAergic synapses in hippocampal neurons

“…However, its role in GABAergic synapses in pyramidal neurons has not been studied yet. Interestingly, haplodeficiency of the S-SCAM gene is associated with infantile spasms 17 , the most common and severe form of epilepsy in infants and childhood, suggesting the potential pathogenic role of S-SCAM deficiency in GABAergic function 18 . Moreover, S-SCAM transgenic mice showed reduced GABA A receptor α1 levels, specifically in the synaptosomal fraction (biochemical correlates of synapses) without alterations in its total protein levels 13 , indicating the possibility of defects in GABAergic synapses.…”