TY - JOUR
T1 - Glucocorticoid-glucocorticoid receptor-HCN1 channels reduce neuronal excitability in dorsal hippocampal CA1 neurons
AU - Kim, Jiwon
AU - Lei, Yun
AU - Lu, Xin Yun
AU - Kim, Chung Sub
N1 - Funding Information:
We thank Dr. Payne Y. Chang for the behavioral software. This work was supported by Starting Fund from the Medical College of Georgia at Augusta University.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/10
Y1 - 2022/10
N2 - While chronic stress increases hyperpolarization-activated current (Ih) 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 Ih 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 Ih in dorsal but not ventral CA1 region/neurons. Corticosterone-induced upregulation of functional Ih 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 Ih 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.
AB - While chronic stress increases hyperpolarization-activated current (Ih) 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 Ih 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 Ih in dorsal but not ventral CA1 region/neurons. Corticosterone-induced upregulation of functional Ih 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 Ih 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.
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U2 - 10.1038/s41380-022-01682-9
DO - 10.1038/s41380-022-01682-9
M3 - Article
C2 - 35840797
AN - SCOPUS:85134345448
SN - 1359-4184
VL - 27
SP - 4035
EP - 4049
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 10
ER -