Abstract
GABA is the key inhibitory neurotransmitter in the adult central nervous system, but in some circumstances can lead to a paradoxical excitation that has been causally implicated in diverse pathologies from endocrine stress responses to diseases of excitability including neuropathic pain and temporal lobe epilepsy. We undertook a computational modeling approach to determine plausible ionic mechanisms of GABAA-dependent excitation in isolated post-synaptic CA1 hippocampal neurons because it may constitute a trigger for pathological synchronous epileptiform discharge. In particular, the interplay intracellular chloride accumulation via the GABAA receptor and extracellular potassium accumulation via the K/Cl co-transporter KCC2 in promoting GABAA-mediated excitation is complex. Experimentally it is difficult to determine the ionic mechanisms of depolarizing current since potassium transients are challenging to isolate pharmacologically and much GABA signaling occurs in small, difficult to measure, dendritic compartments. To address this problem and determine plausible ionic mechanisms of GABAA-mediated excitation, we built a detailed biophysically realistic model of the CA1 pyramidal neuron that includes processes critical for ion homeostasis. Our results suggest that in dendritic compartments, but not in the somatic compartments, chloride buildup is sufficient to cause dramatic depolarization of the GABAA reversal potential and dominating bicarbonate currents that provide a substantial current source to drive whole-cell depolarization. The model simulations predict that extracellular K+ transients can augment GABAA-mediated excitation, but not cause it. Our model also suggests the potential for GABAA-mediated excitation to promote network synchrony depending on interneuron synapse location - excitatory positive-feedback can occur when interneurons synapse onto distal dendritic compartments, while interneurons projecting to the perisomatic region will cause inhibition.
Highlights
Despite widespread acceptance of GABA as the transmitter of inhibition in the central nervous system, there is plentiful evidence that GABA can cause pathological excitation in the cortex
It is critical to distinguish how intracellular chloride accumulation and increases in extracellular potassium contribute to GABAAmediated excitation, since these levels are coupled through the primary chloride efflux mechanism, the potassium-chloride cotransporter, KCC2 [11] [7] [12] [5], which has been suggested as a potential therapeutic target to suppress pathological states in epilepsy and pain [13]
In order to better understand the underlying ionic mechanisms of GABAA-mediated depolarization in post-synaptic CA1 pyramidal cells, we developed a computational model that incorporates components critical for ion transport to account for electrical activity in the cell, and importantly, for ion homeostasis
Summary
Despite widespread acceptance of GABA as the transmitter of inhibition in the central nervous system, there is plentiful evidence that GABA can cause pathological excitation in the cortex. In experimental slice preparations with glutamatergic blockade, synaptic activation of GABAA receptors at frequencies that mimic rapid physiological firing leads to a reproducible cellular level phenomenon in isolated post-synaptic CA1 pyramidal neurons - paradoxical excitatory depolarization following the expected hyperpolarization [4,5]. This paradoxical depolarization is the apparent trigger that precedes neuronal firing and network synchrony in slices with intact glutamatergic transmission [6]. In order to understand how modulators of KCC2 activity should be used therapeutically, a clearer understanding of how potassium and chloride kinetics contribute to GABAA-mediated excitation is necessary
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