Upregulated HCN currents and reduced intrinsic excitability in prefrontal cortical pyramidal neurons after maternal separation

The prefrontal cortex (PFC) is a core region regulating emotion, is linked to pathological mood disorders, and is a target for antidepressant drugs. Neonatal maternal separation (MS) is an early-life chronic stressor leading to anxiety and depression in adolescence. Previous studies have shown that neonatal MS results in anxiety- and depressive-like behaviors in both animals and humans. However, the underlying electrophysiological mechanism remains largely unknown. The present study aims to investigate the MS-induced change in the intrinsic excitability of layer 5 pyramidal neurons (L5 PNs) in the prelimbic (PrL) cortex of adolescent adult male mice, and to address the restoring effect of ZD7288, a selective antagonist of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel, on the intrinsic excitability of PrL L5 PNs and its ameliorating effect on the depressive-anxiety behaviors induced by MS. Using whole-cell patch clamp recording and behavioral assessments (open-field, elevated-plus maze, forced-swimming, tail-suspension and sucrose-preference tests), we found that the input resistance (Rin) and intrinsic excitability (firing capability) of PrL L5 PNs were reduced in adolescent mice with neonatal MS experience, along with weakened subthreshold membrane potential oscillations (MPOs) and upregulated hyperpolarization-activated cyclic nucleotide-gated (HCN) Ih. The change in the intrinsic excitability induced by up-regulated Ih was causally linked with the anxiety- and depressive-like behaviors, as intra-PrL administration of ZD7288 increased Rin and restored the intrinsic excitability of PrL L5 PNs, and ameliorated the anxiety- and depressive-like behaviors. Hence, this study demonstrated that neonatal MS reduces the intrinsic excitability of PFC-projecting pyramidal cells via upregulating HCN channel activity, and alters the capability of the PFC to regulate emotional behaviors in adolescence. Inhibiting HCN channels with ZD7288 restores the decreased intrinsic excitability and ameliorates the anxiety- and depressive-like behaviors.