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Updated: Jan 11, 2026
Assessment of Perigenital Sensitivity and Prostatic Mast Cell Activation in a Mouse Model of Neonatal Maternal Separation
Published on: August 13, 2015
Upregulated HCN currents and reduced intrinsic excitability in prefrontal cortical pyramidal neurons after maternal
Xing Wang1, Fei Luo1, Baoming Li2
1Laboratory of Prefrontal Cognitive Function and Disorder, School of Life Sciences and Institute of Biomedical Innovation, Nanchang University, Nanchang 330031, China.
Insights
Neonatal maternal separation reduces prefrontal cortex neuron excitability, increasing anxiety and depression. Inhibiting HCN channels with ZD7288 restores excitability and behavior in adolescent mice.
Area of Science:
- Neuroscience
- Behavioral Neuroscience
- Molecular Psychiatry
Background:
- Neonatal maternal separation (MS) is a stressor linked to adolescent anxiety and depression.
- The prefrontal cortex (PFC) regulates emotion and is implicated in mood disorders.
- Electrophysiological mechanisms underlying MS-induced behavioral changes are largely unknown.
Purpose of the Study:
- Investigate MS-induced changes in the intrinsic excitability of prelimbic (PrL) cortex layer 5 pyramidal neurons (L5 PNs) in adolescent mice.
- Assess the effect of ZD7288, a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel antagonist, on PrL L5 PN excitability.
- Evaluate ZD7288's potential to ameliorate MS-induced anxiety- and depressive-like behaviors.
Main Methods:
- Whole-cell patch clamp recordings in adolescent male mice.
- Behavioral assessments including open-field, elevated-plus maze, forced-swimming, tail-suspension, and sucrose-preference tests.
- Intra-prelimbic cortex administration of ZD7288.
Main Results:
- Neonatal MS reduced input resistance and intrinsic excitability of PrL L5 PNs.
- MS was associated with weakened subthreshold membrane potential oscillations and upregulated HCN Ih.
- ZD7288 administration restored PrL L5 PN excitability and ameliorated anxiety- and depressive-like behaviors.
Conclusions:
- Neonatal MS decreases PFC L5 PN intrinsic excitability by upregulating HCN channel activity.
- This excitability change contributes to adolescent anxiety and depressive behaviors.
- Inhibiting HCN channels with ZD7288 offers a potential therapeutic strategy for MS-induced mood disorders.
Abstract:
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.
