Histone deacetylase 4‐dependent regulation of cortical synaptic plasticity and the higher cognitive function during adulthood

Abstract Background It is known that the primary sensory cortex contributes to the higher cognitive function, such as decision‐making. Still, a detailed synaptic mechanism explaining the relationship between sensory input and perceptual decision‐making remains elucidated. Previously, we demonstrated sensory deprivation restores critical‐period‐like synaptic plasticity to the barrel cortex in unilateral infraorbital injury (IO) mice. Method Therefore, we explored the relationship between adult primary synaptic input and perceptual decision‐making in adult IO mice using the head‐fixed texture discrimination test and brain slice patch‐clamp technique. We also explored a molecular mechanism underlying IO‐induced reactivation of thalamocortical (TC) synaptic plasticity in the barrel cortex using immunoblotting of HDAC4 and BDNF as well as AAV/shRNA‐mediating knockdown of HDAC4. Result IO mice learned the spared TC input‐mediated perceptual decision‐making task more effectively than sham‐controls. This improvement in perceptual learning was intimately correlated with spared TC synaptic efficacy. In terms of a possible molecular mechanism for the IO‐induced reactivation of TC synaptic plasticity, histone deacetylase 4 (HDAC4) and brain‐derived neurotrophic factor (BDNF) expression was significantly reduced in layers 4 and 5 of the barrel cortex from PO7 to PO9 in IO mice compared with Sham‐controls. The IO‐induced potentiation of spared TC synaptic efficacy was nearly prevented by blockage of BDNF/TrkB signaling with cyclotraxin B. In addition, HDAC4 knockdown by injecting AAV5‐U6‐mHDAC4‐shRNA‐CMV‐EGFP to the S1 barrel cortex significantly increased BDNF expression and TC synaptic efficacy in the layer4 barrel cortex. Similarly, the application of HDAC4 inhibitor to the S1 barrel cortex via an osmotic pump effectively potentiated TC synaptic efficacy without alteration of excitation/inhibition balance, similar to IO mice. Conclusion These results suggest that the reactivation of synaptic plasticity of primary TC input may regulate the higher cognitive function by modulating HDAC4/BDNF/TrKB signaling during adulthood.