Glucocorticoid-glucocorticoid receptor-HCN1 channels reduce neuronal excitability in dorsal hippocampal CA1 neurons.
Jiwon KimYun LeiXin-Yun LuChung Sub KimPublished in: Molecular psychiatry (2022)
While chronic stress increases hyperpolarization-activated current (I h ) in dorsal hippocampal CA1 neurons, the underlying molecular mechanisms are entirely unknown. Following chronic social defeat stress (CSDS), susceptible mice displayed social avoidance and impaired spatial working memory, which were linked to decreased neuronal excitability, increased perisomatic hyperpolarization-activated cyclic nucleotide-gated (HCN) 1 protein expression, and elevated I h in dorsal but not ventral CA1 neurons. In control mice, bath application of corticosterone reduced neuronal excitability, increased tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) and HCN1 protein expression, and elevated I h in dorsal but not ventral CA1 region/neurons. Corticosterone-induced upregulation of functional I h was mediated by the glucocorticoid receptor (GR), HCN channels, and the protein kinase A (PKA) but not the calcium/calmodulin-dependent protein kinase II (CaMKII) pathway. Three months after the end of CSDS, susceptible mice displayed persistent social avoidance when exposed to a novel aggressor. The sustained behavioral deficit was associated with lower neuronal excitability and higher functional I h in dorsal CA1 neurons, both of which were unaffected by corticosterone treatment. Our findings show that corticosterone treatment mimics the pathophysiological effects of dorsal CA1 neurons/region found in susceptible mice. The aberrant expression of HCN1 protein along the somatodendritic axis of the dorsal hippocampal CA1 region might be the molecular mechanism driving susceptibility to social avoidance.
Keyphrases
- spinal cord
- protein kinase
- neuropathic pain
- spinal cord injury
- working memory
- transcranial direct current stimulation
- cerebral ischemia
- healthcare
- high fat diet induced
- mental health
- poor prognosis
- binding protein
- signaling pathway
- skeletal muscle
- blood brain barrier
- subarachnoid hemorrhage
- endothelial cells
- amino acid
- long non coding rna
- deep brain stimulation
- heat stress