Cdk5 Restricts Adult Visual Cortical Plasticity Through Modulating Inhibitory Neurotransmission

Rapid rewiring and refinement of brain circuits in response to changing stimuli of external environment accelerates the functional maturation of multiple sensory perception during adolescence, a time window defined as critical period. Suppressed anatomic plasticity in adults restricts the recovery of neurological disorders such as stroke and amblyopia, for which restoring experience-dependent ocular dominance plasticity, a well depicted paradigm to probe the malleability of visual cortical connectivity, has been considered a valid strategy to amblyopia treatment. However,the mechanisms that mediate the transformation of plasticity progress are still elusive.Removal of a few brakes, including NgR, CSPG, PirB and lynxl, makes it easier to sculpt brain architecture. To correct enduring visual acuity loss caused by discordant visual input, identifying new factors that restrict visual plasticity in adulthood is an imperative task. Comprehensive application of multiple techniques, I attempted to investigate the potential signaling and approaches that regulate visual plasticity and improve visual acuity, and uncover their underlying mechanisms.Cyclin-dependent kinase 5 (Cdk5) plays a pivotal role in brain development and synaptic plasticity. Dysregulation of Cdk5 activity has been implicated in several neurobiological and neurodegenerative disorders. Intervention of Cdk5 greatly attenuates the detrimental consequences of stroke and improves cognitive functions in AD mouse models. However, the physiological role for Cdk5 signaling in the postnatal maturation of cortical circuitry is largely unknown. In this study, we showed that the protein expression of Cdk5 was correlated with the time course of the critical period in primary visual cortex (VI) of mice. The protein level of Cdk5 decreased when visual plasticity reached to the peak, and was back to normal after the critical period.Pharmacological inhibition or genetic knockdown of Cdk5 in adult mouse V1 successfully reactivated juvenile-like ocular dominance plasticity induced by short-term monocular deprivation. The enhancement of visual plasticity was accompanied by a down-regulation of GABAergic inhibition transmission, as indicated by the reduction of glutamate decarboxylases (GAD65/67) and miniature inhibitory postsynaptic current(mIPSC) amplitude. The expressions of GABAA receptor ?1 and ?2 subunits were comparable in vehicle- and CP681301-treated mice. Besides, the protein levels of BDNF and PNNs was not affected. Cdk5 knockdown also significantly reduced the level of GAD67, while had a mild effect on GAD65 expression. Co-immunoprecipitation experiment further demonstrated that Cdk5 interacted with GAD67. Enhancement of GABA signaling by diazepam impeded the ocular dominance shift induced by Cdk5 inhibitor, which demonstrates that the reduced level of inhibition is involved in the restoration of visual plasticity. These results imply a pivotal role for Cdk5 in the consolidation and stabilization of brain circuits during the development and maturation of visual system. Moreover, the same mechanisms targeting Cdk5 have adaptive value for functional recovery in CNS damage in adulthood, such as that associated with amblyopia, stroke or neurodegenerative diseases.Visual perceptual learning represents another form of plasticity and is perceived as another effective approach for amblyopia treatment. Change in neural plasticity in early visual areas may contribute to the enhancement of circuit connection induced by perceptual learning. However, the mechanisms underlying perceptual learning remain poorly understood. Here, Using home-made trapezoid water maze, I preliminarily explored the potential mechanisms at behavioristic and molecular levels. The mice exhibited remarkable improvement of visual acuity, which could be abolished by reversal learning. Visual perceptual learning did not alter the expressions of GADs. The level of NR2A protein was reduced after visual perceptual training, leaving NR2A mRNA intact. Task rule learning reduced Homerl mRNA expression. Lower level of Pinin mRNA was observed in task learning and perceptual learning group compared with that in control mice. These factors further implied a close correlation between visual perceptual learning and neural plasticity. Further investigating its mechanisms will provide theoretical support for the treatment of neurobio logical disorders.By the study of these projects mentioned above, we explored the possible approaches that could enhance visual plasticity in adult mice. Intervention of Cdk5 rejuvenated experience-dependent ocular dominance plasticity in the adult visual cortex,, which was realized by modulating excitation-inhibition balance. Visual perceptual training altered some factor levels and reversal learning abrogated the enhancement of visual acuity. It is still needed to further investigate their mechanisms, and their generalization and applicability in a variety of sensory systems and species in future studies.