Downregulation of HCN1 Channels in Hippocampus and Prefrontal Cortex in Methamphetamine Re-Exposed Mice With Enhanced Working Memory

Abstract

The hyperpolarization-activated cyclic-nucleotide-gated non-selective cation (HCN) channels play a potential role in the neurological basis underlying drug addiction. However, little is known about the role of HCN channels in methamphetamine (METH) abuse. In the present study, we examined the changes in working memory functions of METH re-exposed mice through Morris water maze test, and investigated the protein expression of HCN1 channels and potential mechanisms underlying the modulation of HCN channels by Western blotting analysis. Mice were injected with METH (1 mg/kg, i.p.) once per day for 6 consecutive days. After 5 days without METH, mice were re-exposed to METH at the same concentration. We found that METH re-exposure caused an enhancement of working memory, and a decrease in the HCN1 channels protein expression in both hippocampus and prefrontal cortex. The phosphorylated extracellular regulated protein kinase 1/2 (p-ERK1/2), an important regulator of HCN channels, was also obviously reduced in hippocampus and prefrontal cortex of mice with METH re-exposure. Meanwhile, acute METH exposure did not affect the working memory function and the protein expressions of HCN1 channels and p-ERK1/2. Overall, our data firstly showed the aberrant protein expression of HCN1 channels in METH re-exposed mice with enhanced working memory, which was probably related to the down-regulation of p-ERK1/2 protein expression.

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

“…HCN1 encodes for the hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (HCN1). HCN1 protein is expressed in the hippocampus (Lee et al, 2019 ), cerebral cortex (Shah, 2014 ; Zhou et al, 2019b ), cerebellum (Luján et al, 2005 ), thalamus (Kanyshkova et al, 2012 ), amygdala (Knoll et al, 2016 ), and entorhinal cortex (Nolan et al, 2007 ). In the brain, they are further spread in layer 5 of neocortical neurons, CA1 and CA3 hippocampal regions, molecular cell layer of the cerebellum (Gravante et al, 2004 ), superficial layers (II/III) of the pyramidal neurons (Santoro and Shah, 2020 ), and parvalbumin-positive interneurons (Notomi and Shigemoto, 2004 ).…”

Cajaninstilbene Acid Ameliorates Cognitive Impairment Induced by Intrahippocampal Injection of Amyloid-β1–42 Oligomers

“…After the probe test, the working memory test was performed in which the platform was relocated every day for three consecutive days (Zhou et al, 2019). Mice were given two trials per day.…”