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 GABA_A 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 GABA_A 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.

Keywords: Epilepsy; GABAergic signaling; Ion channels; Mutations; Non ion channels; Vesicles.

Figure 1.

GABA signaling. In GABAergic interneurons, the neurotransmitter GABA is synthesized from glutamic acid, the principal excitatory neurotransmitter via glutamic acid decarboxylase (GAD). GABA is catabolized by GABA transaminase (GABA-T) which is a membrane bound enzyme expressed by neurons and glia. GABA is released from vesicles in pre-synaptic terminals and activates GABA receptors which include GABA_A receptors and GABA_B receptors. GABA_A receptors hyperpolarize neurons via Cl^- influx. The released GABA is taken up by GABA transporters (GAT-1 and GAT-3) back into pre-synaptic compartments of neurons or into astrocytes.

Figure 2.

Mutations via impairing both pre-synaptic GABA neurotransmitter release and post-synaptic GABA_A receptor expression and function can affect GABAergic signaling. Synaptic transmission relies on the availability of the neurotransmitter; the release of the neurotransmitter by exocytosis and the binding of the normal functional postsynaptic receptor by the neurotransmitter. (A). Interneurons are the main source of cortical modulation over glutamatergic pyramidal cells (PCs). GABA-releasing interneurons as classified by a complex combination of morphological, connectivity, and intrinsic electrophysiological properties and molecular content are critical for cortical inhibition. (B). Mutations associated with epilepsy could impair both the proteins involving in pre-synaptic GABA release and post-synaptic GABA_A receptor function.

Figure 3.

Diverse defects caused by mutations in different genes impair GABA neurotransmitter release. In a given neuron, opening of sodium channels encoded by SCN1A and influx of Na+ cause neuronal firing in which sodium channels are responsible for the rising phase of action potentials. Calcium enters the axon terminal during an action potential, causing release of the neurotransmitter into the synaptic cleft. Synaptogamin acts as a calcium sensor which binds calcium and activates vesicle fusion. Gene mutations that encode proteins involved in the process of vesicle release include but are not limited to PRRT2, SNAP25, syntaxin, STXBP1 and DNM1. Although the biological function of each gene still requires further study, it has been proposed that these proteins are essential for making up the complicated vesicle release machinery for vesicle docking, fusion and exocytosis.