Abstract
Author SummaryThe proper activity of cortical neurons (the brain cells responsible for memory and consciousness) relies on the precise integration of excitatory and inhibitory inputs. The excitation and inhibition (E/I) ratio has to remain constant both in time and strength to prevent neurological and psychiatric diseases. Fast inhibitory synaptic inputs to cortical pyramidal neurons originate from a rich diversity of GABAergic interneurons that operate a strict division of labor by differentially targeting precise regions of the pyramidal neurons. Here, we show that large pyramidal neurons of neocortical layer 5 can unlock the E/I ratio in response to their own activity. Excitatory activity of pyramidal neurons, in the form of membrane depolarization or trains of action potentials, induces a Ca2+-dependent mobilization of nitric oxide, which diffuses to inhibitory synapses and triggers a persistent enhancement of GABA release. Notably, this potentiation of inhibition is specific for synapses originating from parvalbumin (PV)-expressing interneurons that target mainly the perisomatic region of pyramidal neurons. Long-term potentiation of perisomatic inhibition, in turn, changes the ability of pyramidal neurons to integrate excitatory inputs as well as the temporal properties of their own action potential output. Selective plasticity of perisomatic inhibition can thus play a crucial role in cortical activity, such as sensory processing and integration.
Highlights
IntroductionFast GABAergic inhibition is tightly coupled to excitation both temporally and in strength
In the cerebral cortex, fast GABAergic inhibition is tightly coupled to excitation both temporally and in strength
We examined whether layer 5 pyramidal neurons can modulate the strength of GABAergic synapses by postsynaptic depolarization to layer 2/3 pyramidal neurons [11], and if glutamatergic transmission could be altered by postynaptic depolarization protocols
Summary
Fast GABAergic inhibition is tightly coupled to excitation both temporally and in strength This constant balance of opposing forces is necessary for the correct development of cortical sensory receptive fields [1] and allows for the generation and tuning of cortical network activity underlying cognitive functions and complex behaviors [2]. Perturbations in the E/I balance can play a key role in sensory learning and receptive field reorganization [6,7], suggesting it may be necessary to unlock the restrictive gate on the E/I balance. No such cellular mechanisms have been demonstrated. E/I ratios can be state-dependent and regulated according to computational requirements of specific microcircuit pathways
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