Experience-dependent brain plasticity is heightened during developmental critical periods but declines into adulthood, posing a major challenge to recovery of function following injury or disease later in life. A dominant model of critical period plasticity is the change in ocular dominance of neurons in primary visual cortex following monocular deprivation. Recent studies suggest that experience-dependent plasticity of Parvalbumin positive (PV-) GABA interneurons in visual cortex plays a key role in triggering ocular dominance plasticity during the critical period. Importantly, such rapid plasticity of PV cells is limited to the critical period and is not observed in adults. Our pilot study further showed that another major subtype of interneurons expressing Somatostatin (SST) can also modulate ocular dominance plasticity in the adult. These studies underscore the novel role of interneurons in rapidly gating cortical plasticity in adult visual cortex. However, the molecular and circuit mechanisms that limit the rapid plasticity triggered by interneurons in the adult are totally unknown. This proposal deals with this open question to provide new mechanisms of the initial phase of plasticity to effectively re-trigger plastic windows for recovery of cortical function in adults. We turn to proteolytic regulation because tissue plasminogen activator (tPA), a major protease in the brain, is known to rapidly elevate during only critical period but not in adulthood to mediate plasticity. Our preliminary study found that the removal of one endogenous tPA inhibitors called Neuroserpin, enriched in adult PV- and SST-cells, leads to a series of experience-dependent rapid changes to unmask plasticity in adult visual cortex. By combining in vivo extracellular recordings, patch-clamp electrophysiology with optogenetics, pharmacogenetics, and cell-type specific gain/loss of gene expression through genetic and viral techniques in vivo, we will test our hypothesis that proteolytic regulation by an endogenous serine inhibitor, Neuroserpin, gates the sensitivity of PV- and SST- interneurons to rapidly trigger visual cortex plasticity and recovery in adulthood. Proteolytic regulation of rapid plasticity associated with PV-interneurons and SST-interneurons will be examined in Aim1 and Aim2 respectively.
In Aim3, therapeutic potential for recovery from amblyopia by targeting Neuroserpin in interneurons will be tested. Successful completion of this project will illuminate a new molecular mechanism that gates the initial cascade triggering cortical plasticity, which will have direct implications for Amblyopia, a condition with limited adult-applicable cure affecting 2?5% of the human population, but also for brain injury repair, sensory recovery.
This study aims to identify the molecular, cellular, and circuit mechanisms that trigger and confine cortical plasticity to developmental critical period. Identified mechanisms will provide a mechanistic basis for reopening plastic windows for interventions in amblyopia, one of the most common forms of vision loss during infancy, and other brain injuries or diseases for recovery of function in adults.
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