Summary It has been postulated that homeostatic mechanisms maintain stable circuit function by keeping neuronal firing within a set-point range, but such firing rate homeostasis has never been demonstrated in vivo. Here we use chronic multielectrode recordings to monitor firing rates in visual cortex of freely behaving rats during chronic monocular visual deprivation (MD). Firing rates in V1 were suppressed over the first 2 d of MD, but then rebounded to baseline over the next 2–3 d despite continued MD. This drop and rebound in firing was accompanied by bi-directional changes in mEPSC amplitude measured ex vivo. The rebound in firing was independent of sleep-wake state but was cell-type specific, as putative FS and regular spiking neurons responded to MD with different time-courses. These data establish for the first time that homeostatic mechanisms within the intact CNS act to stabilize neuronal firing rates in the face of sustained sensory perturbations.

SUMMARY Homeostatic mechanisms stabilize neural circuit function by keeping firing rates within a set-point range, but whether this process is gated by brain state is unknown. Here, we monitored firing rate homeostasis in individual visual cortical neurons in freely behaving rats as they cycled between sleep and wake states. When neuronal firing rates were perturbed by visual deprivation, they gradually returned to a precise, cell-autonomous set-point during periods of active wake, with lengthening of the wake period enhancing firing rate rebound. Unexpectedly, this resetting of neuronal firing was suppressed during sleep. This raises the possibility that memory consolidation or other sleep-dependent processes are vulnerable to interference from homeostatic plasticity mechanisms.

Highlights d Visual cortical circuits in vivo exhibit criticality, an ideal computational regime d Monocular deprivation disrupts criticality prior to firing rate depression d Criticality is actively re-established as firing rates are maximally depressed d Models suggest inhibitory plasticity as a mechanism of a stable computational regime

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Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss in vitro abolished synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the in vivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which, in turn, may render them more vulnerable to such perturbations.