Sleep-wake-related changes in intracellular chloride regulate plasticity at glutamatergic cortical synapses.

Abstract

Wakefulness and sleep affect the brain's ability to exhibit plastic changes.^1,2 For instance, the potentiation of cortical excitatory synaptic connections is associated with the active period, when animals are mainly awake.^3,4,5,6,7 It is unclear, however, how changes in neuronal physiology that are associated with sleep-wake history, affect the mechanisms responsible for synaptic plasticity. Recently, it has been shown that sleep-wake history alters transmembrane chloride (Cl^-) gradients in cortical pyramidal neurons via Cl^- cotransporter activity, which shifts the reversal potential for gamma-aminobutyric acid (GABA) type A receptors (E_GABAA) when assessed in vivo and in vitro.^8,9 Hyperpolarizing E_GABAA values are associated with recent sleep, whereas depolarizing E_GABAA values are associated with recent waking. Here, we demonstrate that sleep-wake-history-related changes in E_GABAA affect membrane potential dynamics and glutamatergic long-term potentiation (LTP) elicited by spiking activity in pyramidal neurons of the mouse cortex. Reducing the depolarized shift in E_GABAA during the active period reduces the potentiation of cortical excitatory synapses onto layer 5 (L5) pyramidal neurons. Depolarized E_GABAA values facilitate LTP induction by promoting residual membrane depolarization during synaptically evoked spiking. Changes in LTP induction associated with sleep-wake history can be reversed by switching the E_GABAA-dependent effects, either by using direct current injection to counteract the effects upon residual membrane potential depolarization or by modulating cotransporters that regulate E_GABAA. We conclude that E_GABAA dynamics provide a functional link between changes in a neuron's physiology that are associated with sleep-wake history and the mechanisms responsible for the induction of glutamatergic synaptic plasticity.