Early temporary windows of heightened brain plasticity called critical periods sculpt neural circuits and contribute to adult behaviors. Such heightened plasticity declines into adulthood. A clinically central issue is that this limits recovery of function later in life. The long-term goal of this study is to discover new regulatory mechanisms of plasticity to provide therapeutic targets to re-open plastic windows in the adult brain. One of the best-studied models of a critical period is the enduring loss of responsiveness in primary visual cortex (V1) to an eye deprived of vision, resulting in amblyopia (a loss of visual acuity), affecting 2?4% of the population and without a known cure in adulthood. Recently, the nicotinic acetylcholine receptor (nAChR) system and its endogenous modulators that belong to Lynx family have emerged as key regulators of plasticity in adult V1. Previous work showed that Lynx1 increases in expression after the critical period and acts as a brake to limit V1 plasticity in the adult brain. In preliminary studies, Lypd6, another Lynx family protein, was found to act as a positive modulator of adult plasticity. However, the specific mechanisms of plasticity regulated by the Lynx family members, such as responsible cell-types, nAChR subtypes, and neural circuits regulated, etc, are totally unknown. The objective of this study is to identify novel mechanisms of plasticity by focusing on Lynx1 and Lypd6, which represent a new class of plasticity regulators that modulate nAChR signals. Strikingly, these two Lynx family members have opposite expression patterns in two major subtypes of GABAergic interneurons: while Lynx1 is primarily expressed in parvalbumin interneurons, Lypd6 is exclusively expressed in somatostatin interneurons. Furthermore, viral manipulations of Lynx1 and Lypd6 in GABAergic neurons but not in glutamatergic neurons modulate adult V1 plasticity, making them unique targets to dissect the mechanisms of plasticity linking the nAChR and GABAergic systems. We hypothesize that Lynx1 and Lypd6 have distinct roles on GABAergic interneurons to regulate adult plasticity through modulation of specific nAChRs, and that the Lynx family can be an effective pre-clinical therapeutic target for treating amblyopia. By combining cell-type specific gain/loss of gene expression through genetic and viral techniques with in vivo electrophysiology assisted by optogenetic tagging for cell-type specific measurements, and in vivo two- photon imaging of structural plasticity, we expect to identify the specific mechanisms of plasticity regulated by the Lynx family members, such as responsible cell-types, the nAChR subtypes, and neural circuits. Identification of such mechanisms would allow exploiting manipulations of the Lynx system in order to facilitate functional recovery after the end of the critical period, which would in turn lead to new opportunities to treat amblyopia and other disorders of cortical plasticity.
This proposal aims to uncoverthe mechanisms of the adult visual cortex plasticity regulated by a new class of proteins that belong to Lynx family that endogenously regulate nicotinic acetylcholine system. The identified mechanisms will provide novel therapeutic targets for interventions in amblyopia,one of the most common forms of vision loss during infancy, and potentially other brain disorders.
