Abnormal excitability of hippocampal neurons may lead to dysfunction of neural circuits and then causes cognitive impairments in Alzheimer's disease (AD). However, the underlying mechanisms remain to be fully elucidated.

Our data suggest that dysregulation of HCNs, particularly HCN2, contributes to the abnormal excitability of CA1 PNs in AD mice and probably in AD patients as well, and thus provide new insights into the mechanisms underlying the aberrant activity or excitability of hippocampal neurons in AD.

Electrophysiology was performed to examine the intrinsic excitability of CA1 neurons and the activity of the hyperpolarization-activated cyclic nucleotide-gated ion channels (HCNs) of CA1 neurons in wild type (WT) and hAPP-J20 mice. The activity of CA1 pyramidal neurons (PNs) was modulated with chemogenetics. The activity of HCNs was regulated with nonselective facilitator (cAMP) or inhibitor (ZD7288) of HCNs. Immunohistochemical staining or western blotting were performed to examine the expression of HCN1 and HCN2 in the hippocampus of WT and hAPP-J20 mice, or AD patients and non-AD controls. AAVs were injected to specifically modulate the expression of HCN2 in dorsal CA1 (dCA1) PNs. Cognitive performance of mice was assessed with behavioral tests.

dCA1 PNs were more excitable in hAPP-J20 mice, but the excitability of PNs in the ventral CA1 (vCA1) or PV neurons was comparable between WT and hAPP-J20 mice. The activity of the HCNs was reduced in dCA1 PNs of hAPP-J20 mice, and pharmacologically increasing the activity of HCNs attenuated the hyperexcitability of dCA1 PNs in hAPP-J20 mice, suggesting that the reduced activity of HCNs is associated with the hyperexcitability of dCA1 PNs in hAPP-J20 mice. The expression of HCN2 but not HCN1 was reduced in the hippocampus of hAPP-J20 mice, and the expression of HCN2 was also reduced in the hippocampus of AD patients, suggesting that dysregulation of HCN2 is associated with the reduced activity of HCNs in AD. Overexpressing HCN2 rescued the activity of HCNs, attenuated the hyperexcitability of dCA1 PNs and improved memory of hAPP-J20 mice, and knocking down HCN2 impaired the function of HCNs, increased the excitability of dCA1 PNs and led to memory deficits in WT mice. Conclusions: Our data suggest that dysregulation of HCNs, particularly HCN2, contributes to the abnormal excitability of CA1 PNs in AD mice and probably in AD patients as well, and thus provide new insights into the mechanisms underlying the aberrant activity or excitability of hippocampal neurons in AD.