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

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 (EGABAA) when assessed in vivo and in vitro.8,9 Hyperpolarizing EGABAA values are associated with recent sleep, whereas depolarizing EGABAA values are associated with recent waking. Here, we demonstrate that sleep-wake-history-related changes in EGABAA 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 EGABAA during the active period reduces the potentiation of cortical excitatory synapses onto layer 5 (L5) pyramidal neurons. Depolarized EGABAA 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 EGABAA-dependent effects, either by using direct current injection to counteract the effects upon residual membrane potential depolarization or by modulating cotransporters that regulate EGABAA. We conclude that EGABAA 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.