Role of COP1 in dendritic spines, cognition and stress resilience

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Maintenance of healthy dendritic spine and synapse function is essential for normal brain function. The number of dendritic spines is precisely controlled and coordinated by synaptic activity to ensure functional brain network integrity. It is well-established that disruptions of the density, shape and size of dendritic spines are associated with psychiatric disorders. The medial prefrontal cortex (mPFC) is an information processing center and forms brain circuit with hippocampus. The hippocampus is well established as an important brain area for cognition. This cognitive dysfunction found in psychiatric disorders may result from disruptions of the hippocampal-prefrontal cortex circuit. The hippocampus and mPFC are vulnerable to stress. Stress is a risk factor for psychiatric disorders such as depression. Chronic stress-induced cognitive deficit is accompanied by a decrease in spine density and impaired synaptic plasticity in the pyramidal neurons of the rodent mPFC and hippocampal CA1 area. But the underlying mechanisms are poorly understood. Tight regulation of protein degradation is critical for normal brain function. Maintaining normal ubiquitin-proteasome system (UPS), which regulates protein degradation, is necessary for proper development of the brain, synapse formation and plasticity. Dysregulation of UPS results in diseases, e.g. mutations in E3 ligase cause psychiatric disorders. Constitutive photomorphogenesis protein 1 (COP1), an E3 ubiquitin ligase, is a critical and negative regulator of its various substrates. COP1 plays an essential role in mouse brain development, but function of COP1 in the adult brain is unknown. Genome-wide association studies showed that COP1 is a risk factor for anxiety, bipolar disorder, depression, and autism. Our preliminary studies showed that COP1 is localized to principal neurons of the mouse prefrontal cortex; COP1 deletion in the principal neurons of the forebrain cortex and hippocampal CA1 in COP1 conditional knockout (Cop1CKO) mice caused an increase in spine density and an enhancement in excitatory synaptic functions in these neurons; these Cop1CKO mice show enhanced cognitive functions and resilience to chronic stress. These preliminary results raise our hypothesis that COP1 plays an important role in dendritic spines, cognition and stress resilience. Our aims are to test this hypothesis: Determine the role of COP1 in spine formation and synaptic functions using Cop1cko mice and WT littermate controls, determine the role of COP1 in cognition and stress resilience, and identify significant substrates through which COP1 affects dendritic spines, cognition and stress resilience. Spatial memory and recognition memory are related to stress and stress-related disorders, and align with declarative memory construct in cognitive system domain of the Research Domain Criteria (RDoC). The results from this study may enhance our understanding of spine formation, cognition, stress resilience and lead to the development of novel interventions for reversing cognitive impairments, enhancing stress resilience, and for treating stress-related disorders. The outcomes of this study are associated with mental health.