HCN Channels: From the Role in Chronic Cerebral Hypoperfusion-Induced Cognitive Impairments to a New Therapeutic Target for Vascular Dementia

Abstract

Hyperpolarization-activated cyclic nucleotide-gated channels are concentrated in cortical and hippocampal pyramidal cell dendrites, where they play an important role in determining synaptic integration and plasticity phenomena. These channels have been suggested to be involved in physiological processes such as cognition as well as pathophysiological states such as epilepsy, pain, Parkinson's disease (PD) and Alzheimer's disease (AD). Recent evidences from our own researches have suggested that the learning and memory impairments caused by chronic cerebral hypoperfusion (CCH) are associated with a change of HCN1/HCN2 expression; therefore these channels may also be therapeutic targets for treatment of vascular dementia. Keywords: Vascular dementia; HCN channels; Chronic cerebral hypoperfusion ReviewVascular dementia (VaD) is the second leading form of dementia after Alzheimer's disease (AD) among western countries [1]. It is a progressive disease caused by cerebrovascular diseases with the pathologic features of reduced blood flow in the brain that affects cognitive abilities [2][3][4]. Accordingly, the cognitive impairment associated with vessel disorders is an increasingly important and recognised area of the medicine of VaD patients. CCH is a common consequence of various cerebral vascular disorders and hemodynamic changes that contributes to the risk of VaD. In rodents, the bilateral common carotid artery occlusion (2VO) model is so far the most effective and frequently-used experimental model to evaluate the relation between chronic cerebral hypoperfusion and vascular diseaserelated dementia [2,[5][6][7]. However, the progress on understanding the basis of the disease and developing treatments is not encouraging. There are no drugs licensed for the treatment of VaD. In this context, we reviewed the discoveries from our own research based on 2VO model that the role of HCN channels in CCH-induced cognitive impairments and hypothesise a new therapeutic target toward developing novel treatments for dementia of vascular origin.HCN channels are cation channels that open at membrane voltages close to resting membrane potentials and are directly regulated by the binding of cAMP. It was identified in the late 1970s in sinoatrial node cells and neurons [8][9][10][11]. The HCN channel family is comprised of four subtypes (HCN1-4). The predominant forms in the hippocampus and cortex are HCN1 and HCN2 [12,13]. In pyramidal and neocortical neurons, they show a large gradient of expression that can be 60-fold increase from somatic to distal apical dendritic membranes [14]. The channels are formed by heteromeric or homomeric complexes and carry the hyperpolarization-activated current, Ih. In neuronal dendrites, Ih is proposed to be responsible for several important cellular functions and plays a fundamental role in controlling cellular excitability, rhythmic activity, dendritic integration, synaptic transmission, and plasticity phenomena [15][16][17] that participates in the pathogenic mechanism of certain neurolog...