Regulation of Inhibitory Signaling at the Receptor and Cellular Level; Advances in Our Understanding of GABAergic Neurotransmission and the Mechanisms by Which It Is Disrupted in Epilepsy

Abstract

Inhibitory signaling in the brain organizes the neural circuits that orchestrate how living creatures interact with the world around them and how they build representations of objects and ideas. Without tight control at multiple points of cellular engagement, the brain’s inhibitory systems would run down and the ability to extract meaningful information from excitatory events would be lost leaving behind a system vulnerable to seizures and to cognitive decline. In this review, we will cover many of the salient features that have emerged regarding the dynamic regulation of inhibitory signaling seen through the lens of cell biology with an emphasis on the major building blocks, the ligand-gated ion channel receptors that are the first transduction point when the neurotransmitter GABA is released into the synapse. Epilepsy association will be used to indicate importance of key proteins and their pathways to brain function and to introduce novel areas for therapeutic intervention.

Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy

“…At the same time, in soc neurons, there was a decrease in the expression of the genes cav1.3, kir4.1, bkca1, bkcb1, and bkcb4 encoding the alpha subunit of the L-type Ca 2+ channel, the Kir4.1-type K + channel, and calcium subunits-activated BK channels (Figure 7C). The ratio of excitatory glutamate receptors and inhibitory GABA receptors might contribute to hyperexcitation and epileptiform activity [18][19][20]. In "phenotype" soc neurons, a decrease in the expression level of the gabra1 (GABA-A receptor) and gria2 (GluA2 subunit of AMPA receptors) genes, and an increase in the level of the grin2a and grin2b genes (Figure 8B), was observed.…”

“…The expression level of the GluN2A and GluN2B subunits, as shown by immunocytochemical staining (Supplementary Figure S1B), was significantly higher in soc neurons (Figure 9C). The ratio of excitatory glutamate receptors and inhibitory GABA receptors might contribute to hyperexcitation and epileptiform activity [18][19][20]. In "phenotype" soc neurons, a decrease in the expression level of the gabra1 (GABA-A receptor) and gria2 (GluA2 subunit of AMPA receptors) genes, and an increase in the level of the grin2a and grin2b genes (Figure 8B), was observed.…”

Research advances in huntingtin-associated protein 1 and its application prospects in diseases

“…GABA A Rs are considered among the most important receptors involved in the induction of epilepsy. Disruption of synaptic aggregation and a reduction in the number of GABA A Rs at the membrane lead to excitatory potentiation and abnormal network oscillations in the neuronal circuits of epileptic patients (Tipton and Russek, 2022). As a key mediator in the transport of GABA A Rs, HAP1 interacts directly with GABA A Rs, prevents lysosomal degradation of internalized GABA A Rs and facilitates the recirculation of internalized GABA A Rs to synapses, which is critical for controlling rapid inhibitory synaptic transmission.…”

Electrophysiological findings in migraine may reflect abnormal synaptic plasticity mechanisms: A narrative review

“…Synaptic plasticity is responsible for synapse remodelling during experience in mature neurons. From research on neurodevelopmental and neurological disorders, such as epilepsy and autism (179), it is well known that genetic mutations or pathology can lead to altered excitatory or inhibitory neurotransmission or impaired synaptogenesis, which typically results in synaptic plasticity deficits (180).…”