SUBANESTHETIC KETAMINE INDUCES AMPA-SILENT SYNAPSES AND RESTORES JUVENILE OCULAR DOMINANCE PLASTICITY IN ADULT MOUSE PRIMARY VISUAL CORTEX (V1)

Neurodevelopmental disorders are caused by impaired experience-dependent refinement of neural networks during development. We recently established that AMPA receptor-silent synapse maturation closes the critical period (CP) for ocular dominance plasticity (ODP) in mouse V1, consolidating proper excitatory synapses. In search for mechanisms to reopen CP-plasticity, we here explore the potential of subanesthetic ketamine on silent synapse generation.
We first performed patch clamp recordings in slices of adult mouse V1 to quantify the fraction of AMPA-silent synapses following in vivo treatment with subanesthetic ketamine or saline. In fact, ketamine-treatment increased silent synapse percentage from 1.7±0.04% to 40.2±0.05% (p<0.001, t-test). Next, we measured ODP using intrinsic signal optical imaging in vivo in adult mouse V1 following ketamine/saline treatment after 4 days of monocular deprivation (MD). As hypothesized from the in vitro electrophysiological data, ketamine- but not saline- treatment restored ODP in adult mouse V1: after MD, both eyes activated V1 more equally, and the ocular dominance index, which quantifies V1-activation through the ipsi- and contralateral eye, was reduced from 0.25±0.02 to 0.06±0.03 (p=0.0052, one-way ANOVA). Notably, ODP was mediated by a decreased contralateral eye-induced V1-activation (before/after MD: 2.8±0.02/1.8±0.22, p=0.007, 2-way ANOVA), indicating the presence of juvenile ODP. In contrast, in saline-treated mice, V1 remained dominated by the contralateral eye also after MD (before/after MD: 2.9±0.3/2.3±0.2, p=0.11, 2-way ANOVA), indicative of absent ODP. Thus, treatment with subanesthetic ketamine can restore juvenile ODP in adult mouse V1 via silent synapse induction.