the regulation of critical period for ocular dominance plasticity

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Gu, Yu
Quinlan, Elizabeth M
The experience dependent plasticity of stimulus selectivity, including ocular dominance plasticity, is highest during a postnatal critical period. The developmental constraint on this plasticity is thought to underlie the inability to recover from amblyopia in adults, which has generated interest in understanding the mechanisms for the initiation and termination of the critical period. Previously, it had been shown dark exposure initiated in adulthood (P90) reactivates robust ocular dominance plasticity in the visual cortex. In this thesis, I showed dark exposure initiated earlier (P45-55) in postnatal development does not facilitate rapid ocular dominance plasticity, demonstrating the presence of a refractory period for the regulation of synaptic plasticity by visual deprivation. Using an anesthetic other than barbiturate revealed that ocular dominance plasticity persists much later in postnatal development (up to ~ P55), which can be inhibited by diazepam, a positive allosteric modulator of ligand bound GABAARs, suggesting a regulatory mechanism that is upstream of inhibitory synaptic transmission. To test this, I used NARP and NRG1-ErbB4 to manipulate excitation onto FS (PV) INs, a major subtype of inhibitory neurons which exert powerful perisomatic inhibition onto principal neurons in the visual cortex. NARP is an activity dependent pentraxin which has been shown to accumulate AMPARs onto FS (PV) INs. Transgenic deletion of NARP decreases the number of excitatory synaptic inputs onto FS (PV) INs and reduces net excitatory synaptic drive onto FS (PV) INs. Accordingly, the visual cortex of NARP -/- mice is hyperexcitable and unable to express ocular dominance plasticity, although many aspects of visual function are normal. NRG1 is an activity dependent neutrophic factor which is proposed to promote excitability and excitatory synaptogenesis onto FS (PV) INs. Pharmacological manipulation of the NRG1-ErbB4 pathway can regulates the excitability of FS and RS neurons in visual cortex, and promotes or inhibits the expression of ocular dominance plasticity, depending on the state of maturation of cortical circuitry. Importantly, manipulations of the excitability of FS and RS neurons into the permissive range can enable the expression of ocular dominance plasticity, at any age, which holds promise to future treatment of clinical disorders such as amblyopia.