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Summary: A fundamental challenge of neuroscience is to understand how a single neuron responds to multiple synaptic inputs effectively and reliably. In primary visual cortex, repeated stimuli to one eye elicit neuronal responses of inherent variability and reliability. However, it remains unclear how this monocular variability and reliability contribute to the establishment of effective and reliable binocular responses and what drives this development. In this study, using in vivo multichannel extracellular recordings, we demonstrate binocular responses in adult mouse visual cortex exhibit low variability and high reliability. This response characteristic is immature during the critical period of binocular vision development. In amblyopic mice, the maturation of binocular variability and reliability is disrupted, and this defect can be partially rescued by enhancing cortical plasticity via dark exposure. In conclusion, the development of cortical response variability and reliability depends on the normal binocular visual experience, which is further regulated by cortical plasticity.

Binocular matching of orientation preference between the two eyes is a common form of binocular integration that is regarded as the basis for stereopsis. How critical period plasticity enables binocular matching under the guidance of normal visual experience has not been fully demonstrated. To investigate how critical period closure affects the binocular matching, a critical period prolonged mouse model was constructed through the administration of bumetanide, an NKCC1 transporter antagonist. Using acute in vivo extracellular recording and molecular assay, we revealed that binocular matching was transiently disrupted due to heightened plasticity after the normal critical period, together with an increase in the density of spines and synapses, and the upregulation of GluA1 expression. Diazepam (DZ)/[(R, S)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP)] could reclose the extended critical period, and rescue the deficits in binocular matching. Furthermore, the extended critical period, alone, with normal visual experience is sufficient for the completion of binocular matching in amblyopic mice. Similarly, prolonging the critical period into adulthood by knocking out Nogo-66 receptor can prevent the normal maturation of binocular matching and depth perception. These results suggest that maintaining an optimal plasticity level during adolescence is most beneficial for the systemic maturation. Extending the critical period provides new clues for the maturation of binocular vision and may have critical implications for the treatment of amblyopia.