Chronic Cerebral Hypoperfusion-induced Dysregulations of Hyperpolarization- activated Cyclic Nucleotide-gated, KCNQ and G Protein-coupled Inwardly Rectifying Potassium Channels Correlated with Susceptibility and Unsusceptibility to Anxiety Behaviors

Abstract

Background: Cerebrovascular lesions could induce affective disorders; however, the depression- and anxiety-related symptoms caused by chronic cerebral hypoperfusion (CCH) and the roles of different hyperpolarization-activated cyclic nucleotide-gated (HCN), KCNQ and G protein-coupled inwardly rectifying potassium (GirK) channel subunits in these pathological processes have been poorly elucidated so far. Objective: To investigate the behavioral change and the alteration of HCN, KCNQ, and GirK subunits in amygdale of rats suffered from CCH. Methods: Permanent bilateral occlusion of the common carotid arteries was used to induce CCH. Anxiety and depression levels were assessed by the elevated plus maze test, sucrose preference test and forced swimming test to classify rats as highly anxious or depressive ‘susceptibility’ vs. ‘unsusceptibility’. The expression of brain derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrKB), HCN1/2, KCNQ2/3, and GirK1/2/3 were quantified by Western blotting. Results: The mainly emotional change caused by 4 weeks of CCH is likely to be anxiety-like behavior (50%), accompanied by a down-regulation of BDNF and TrKB expression in amygdale. The increase of HCN1 and decrease of KCNQ3 expression in amygdale may be factors to blame for anxiety-like symptom caused by CCH, and the increase of KCNQ2 and Girk1 expression in amygdale may play a role in resilience to the anxiety induced by CCH. Conclusion: The different subunits of HCN, KCNQ and GirK channels in amygdale may contribute to distinct response to aversive stimuli or stress induced by CCH that evokes divergent influence on anxiety-like behavior in rats.

Regulatory Molecules of Synaptic Plasticity in Anxiety Disorder

“…62 , 63 Studies also show that blocking HCN can promote the development of anxiety or depression behaviors. 64 , 65 Therefore, HCN is beneficial for exploring potential drug targets for anxiety therapy. At present, four mammalian subtypes (HCN1–4) have been identified, which are all composed of tetramers.…”

“…Cerebrovascular lesions could induce affective disorders, and the increase of HCN1 and decrease of potassium channel subunit 3 expression in amygdale may be factors to blame for anxiety-like symptom caused by cerebrovascular lesions. 65 Studies also showed that the change in synaptic ultrastructure might be caused by lower BDNF, while the high expression of HCN1 downregulated the synthesis of BDNF mRNA in the brain. 69 Blocking HCN could alleviate anxiety-like behavior of rats by improving learning ability, which might be associated with the overexpression of BDNF–mTOR signaling pathways and synaptic plasticity.…”

Behavioral and neuro-functional consequences of eliminating the KCNQ3 GABA binding site in mice

“…Given the importance of M-current in controlling neuronal excitability, neuronal KCNQ channels have emerged as promising targets for the treatment of various disorders related to hyperexcitability. These include conditions such as acute and neuropathic pain, migraine pain, anxiety, epilepsy, stroke, and traumatic brain injury ( Singh et al, 1998 ; Wua and Dworetzky, 2005 ; Munro and Dalby-Brown, 2007 ; Bierbower et al, 2015 ; Li et al, 2019 ; Vigil et al, 2020 ; Zhou et al, 2022 ). The inhibitory effects of presynaptic KCNQ2/3 channels on neuronal excitability have been partially attributed to their modulation of the release of GABA, the primary inhibitory neurotransmitter in the central nervous system ( Martire et al, 2004 ; Peretz et al, 2007 ).…”