Subanesthetic ketamine reactivates adult cortical plasticity to restore vision from amblyopia

A single dose of ketamine reactivates visual cortical plasticity in adult mice and restores visual acuity defects caused by amblyopia. Ketamine reduces neuregulin-1 (NRG1) expression in parvalbumin-expressing (PV) inhibitory neurons, leading to rapid and sustained decreases in synaptic inhibition to excitatory neurons and reduced synaptic excitation to PV neurons. These effects are blocked by adding NRG1 or removing its receptor from PV neurons. The findings indicate that ketamine's reactivation of adult visual cortical plasticity works through cortical disinhibition via downregulation of PV-specific NRG1 signaling, revealing a neural plasticity-based mechanism for functional recovery from adult amblyopia.

Study at a glance

Abstract

Subanesthetic ketamine evokes rapid and long-lasting antidepressant effects in human patients. The mechanism for ketamine’s effects remains elusive, but ketamine may broadly modulate brain plasticity processes. We show that single-dose ketamine reactivates adult mouse visual cortical plasticity and promotes functional recovery of visual acuity defects from amblyopia. Ketamine specifically induces down-regulation of neuregulin-1 (NRG1) expression in parvalbumin-expressing (PV) inhibitory neurons in mouse visual cortex. NRG1 downregulation in PV neurons co-tracks both the fast onset and sustained decreases in synaptic inhibition to excitatory neurons, along with reduced synaptic excitation to PV neurons in vitro and in vivo following a single ketamine treatment. These effects are blocked by exogenous NRG1 as well as PV targeted receptor knockout. Thus ketamine reactivation of adult visual cortical plasticity is mediated through rapid and sustained cortical disinhibition via downregulation of PV-specific NRG1 signaling. Our findings reveal the neural plasticity-based mechanism for ketamine-mediated functional recovery from adult amblyopia.