Presynaptic mechanisms of neuronal plasticity and their role in epilepsy

Abstract

Synaptic communication requires constant adjustments of pre- and postsynaptic efficacies. In addition to synaptic long term plasticity, the presynaptic machinery underlies homeostatic regulations which prevent out of range transmitter release. In this minireview we will discuss the relevance of selected presynaptic mechanisms to epilepsy including voltage- and ligand-gated ion channels as well as cannabinoid and adenosine receptor signaling.

RNA Editing—Systemic Relevance and Clue to Disease Mechanisms?

“…Actually, other researchers also highlight the importance of presynaptic GlyRs (for examples see Lee et al, 2009; Kubota et al, 2010; Waseem and Fedorovich, 2010). However, even if GlyRs are expressed at both presynaptic and postsynaptic sites, a small number of presynaptic RNA-edited gain-of-function GlyRs even a single cluster of the non-RNA-edited GlyR α3L splice variant, which contains up to 200 receptor channels (Notelaers et al, 2012), will have a greater impact on the presynaptic membrane potential due to the much smaller volume and hence electrical capacity of this compartment compared to the somatodendritic compartment (Meier et al, 2014). Notably in this context, application of a low glycine concentration (10 μM) to hippocampal slice preparations enhanced the occurrence of epileptiform activity whereas a high glycine concentration (100 μM) attenuated recurrent epileptiform discharge (Chen et al, 2014).…”

“…These divergent effects can be explained by preponderant functional impact of low glycine on presynaptic GlyRs expressed at glutamatergic terminals, resulting in facilitated glutamate release, and massive recruitment of somatodendritic GlyR activation by 100 μM glycine, resulting in tonic inhibition, respectively. Based on current evidence we believe that the presynaptic compartment is particularly vulnerable to maladaptive changes in neurotransmitter receptor signaling in disease (for a review see Meier et al, 2014). In the context of the rather low neuronal ambient glycine concentration in the hippocampus, presynaptic RNA-edited GlyRs were indeed shown to facilitate neurotransmitter release and contribute to gain-of-function of the affected neuron types, which elicited neuropsychiatric symptoms like cognitive dysfunction or persistence of contextual fear memory in our animal model.…”

Rare variants in γ‐aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes

“…13 Emerging evidence highlights imbalances of excitatory and inhibitory neurotransmission as a key pathomechanism of epilepsies. 14,15 The c-aminobutyric acid type A receptor (GABA A -R) is a ligand-gated chloride channel mediating fast inhibitory synaptic transmission in the mammalian brain. It consists of a pentameric assembly of different subunits (a [1][2][3][4][5][6] , b 1-3 , c 1-3 , d, e, p, h, q 1-3 ).…”

Neuronal plasticity and epilepsy: modern concepts and mechanisms of epilepsy and depression comorbidity

“…Синаптические коммуникации требуют постоянной «подстройки» пре-и постсинаптических эффективно-стей. Наряду с долговременной синаптической пластич-ностью в основе гомеостатической регуляции, предотвра-щающей избыточное высвобождение нейромедиаторов, лежат и сигнальные механизмы, опосредованные канна-биноидными и аденозиновыми рецепторами [6]. Предпо-лагается, что гомеостатические механизмы активно задей-ствованы в эпилептическом мозге и призваны восстано-вить нормальную активность нейронов и сетей, противо-действуя механизмам эпилептогенеза.…”