Chloride dynamics alter the input-output properties of neurons

Abstract

Fast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal inputoutput function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were entirely mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition. Author SummaryThe fundamental unit of computation in the brain is the neuron, whose output reflects information within the brain. A determining factor in the transfer and processing of information in the brain is the modulation of activity by inhibitory synaptic inputs. Fast synaptic inhibition is mediated by the neurotransmitter GABA binding to GABAA receptors, which are permeable to chloride ions. How changes in chloride ion concentration affect neuronal output is an important consideration for information flow in the brain that is currently not being thoroughly investigated. In this research, we used multi-compartmental models of neurons to link the deleterious effects that accumulation of chloride ions can have on inhibitory signalling with changes in neuronal ouput. Together, our results highlight the importance of accounting for changes in chloride concentration in theoretical and computer-based models that seek to explore the computational properties of inhibition.

NKCC1 and KCC2: Structural insights into phospho-regulation

“…relatively small increases in [Cl − ] i will depolarize E Cl toward V rest (Currin et al, 2020). This significantly reduces or even eliminates hyperpolarizing inhibition thus affecting the inputout function of neurons and modify or even degenerate neuronal function (Currin et al, 2020).…”

“…relatively small increases in [Cl − ] i will depolarize E Cl toward V rest (Currin et al, 2020). This significantly reduces or even eliminates hyperpolarizing inhibition thus affecting the inputout function of neurons and modify or even degenerate neuronal function (Currin et al, 2020). Computational models of a mature CA1 pyramidal neuron revealed that shifting the reversal potential of GABA (E GABA ) by only ∼2.5 mM (∼ to 5 mV from −75 to −70 mV) results in an increase in action potential firing by 39% (Saraga et al, 2008).…”

“…The other conformational state (state 2) provides access to phospho-sites that are targeted by the action of this reagent, leading to state 3 (Figure 5). This can result in distinct Cl − transport activities, reflecting the past history, and ultimately in different transformations of the neuronal input-output function (Currin et al, 2020), which relate to phenomena as important and diverse as synaptic integration, the flow of information through neuronal circuits, learning and memory, neural circuit development and diseases. The phospho-site enriched unstructured regions are therefore 10.3389/fnmol.2022.964488 ideally suited to act as a processor to regulate the output of the transporters by computing signaling from ongoing and past physiological states.…”