Cdk5 Regulates Experience-Dependent Visual Plasticity Through PV+ Neurons In Adult Mice

In early development,brain circuits are rapidly rewired and refined in response to changing stimuli of external environment.As the brain matures,cortical circuits tend to stabilize,which means the cortex is less able to repair damage.So far,several nervous system diseases are still urgent medical problems for human beings,which bring a lot of pain to patients and their families.Enhancing the plasticity of adult cortex is a potential therapeutic strategy,which will provide assistance for the treatment of these diseases.The mouse visual cortex has emerged as a model system to investigate plasticity.In this study,we used a variety of experimental techniques to explore how to improve visual plasticity in adult mice and its underlying mechanisms.Cyclin-dependent kinase 5(Cdk5)is a proline-directed serine/threonine kinase expressed abundantly in post-mitotic neurons and plays a vital role in various brain regions.Our previous work has showed that inhibition of Cdk5 activity was sufficient to reactivate juvenile-like,experience-dependent ocular dominance(OD)plasticity in adults.In present study,this finding was confirmed with optical imaging techniques.We showed that Cdk5 inhibition led to an increase in the proportion of the GluN2B subunit of the N-methyl-D-as-partate(NMDA)receptor(NR2B protein)of synaptosomes and NR2B-mediated currents in the primary visual cortex(V1).Moreover,both WM-LTP(white matter-long-term potentiation)and iLTD(long-term depression of inhibitory responses),which had disappeared in adult visual cortex,could be reinduced after inhibiting Cdk5,suggesting the rejuvenation of inhibitory neurotransmission.Immunohistochemical results showed that Cdk5 was highly expressed in various subtypes of the primary visual cortex.By using RNA interference,we specifically knocked down Cdk5 in different types of neurons in the visual cortex.We demonstrated that cell-type specific knockdown of Cdk5 in PV(parvalbuminexpressing)neurons of V1,but not in Pyr(pyramidal,excitatory neurons),SST(somatostatin-expressing)or VIP(vasoactive intestinal peptide-expressing)neurons,could reactivate experience-dependent OD plasticity,which was accompanied by a decrease in the resting membrane potential and firing rate of action potential and an increase in threshold current of PV neurons.In particular,the OD plasticity induced by Cdk5 inhibitor was reversed by increasing the activity of PV neurons in the visual cortex.In addition,Cdk5 inhibitors reduced Otx2 protein expression in the visual cortex of adults,suggesting that inhibition of Cdk5 activity reduced the inhibitory level of the visual cortex.These results suggest that PV-based inhibitory circuit is the main target for Cdk5 to regulate the visual plasticity of adult mouse.VPL(visual perceptual learning)is a process in which the adult neural system can achieve long-term enhancement through continuous visual tasks without age limit.CRH(also referred to as corticotropin-releasing factor,CRF)is an important member of the HPA(hypothalamic-pituitary-adrenal)axis in the stress response.CRH is widely distributed in visual cortex,but its function is unknown.Our previous work has shown that CRH neurons co-locate with non-PV inhibitory neurons in the visual cortex.The chemogenetic down-regulation of the activity of CRH neurons in the visual cortex enhanced the visual perceptual learning capability of mice,while downregulation of the activity of PV neurons had no significant effect.The results indicate that the improvement of VPL ability is not achieved simply by regulating the inhibitory level.In addition,local application of CRH in V1 could lead to an increase in the neuronal activity and a decrease in the orientation selectivity.The findings reveal that CRH neurons in the visual cortex mediate the effect of stress on visual function,and provide a basis for the crosstalk between stress system and visual system.In conclusion,Cdk5 and CRH regulate the plasticity of visual cortex in different ways.The effect of the former is cell-specific,and down-regulation of its activity in PV neurons in visual cortex restores juvenile visual plasticity in adult mice.The effect of the latter on visual plasticity is independent of PV neurons.Down-regulation of CRH neuron activity improves visual perceptual learning ability of adult mice,while increasing its activity affects visual information processing ability.These findings provide a better understanding of neural plasticity in adult visual cortex and may inspire new treatment for neuropathic disease.