Abstract
Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) in the nervous system are implicated in a variety of neuronal functions including learning and memory, regulation of vigilance states and pain. Dysfunctions or genetic loss of these channels have been shown to cause human diseases such as epilepsy, depression, schizophrenia, and Parkinson's disease. The physiological functions of HCN1 and HCN2 channels in the nervous system have been analyzed using genetic knockout mouse models. By contrast, there are no such genetic studies for HCN3 channels so far. Here, we use a HCN3-deficient (HCN3−/−) mouse line, which has been previously generated in our group to examine the expression and function of this channel in the CNS. Specifically, we investigate the role of HCN3 channels for the regulation of circadian rhythm and for the determination of behavior. Contrary to previous suggestions we find that HCN3−/− mice show normal visual, photic, and non-photic circadian function. In addition, HCN3−/− mice are impaired in processing contextual information, which is characterized by attenuated long-term extinction of contextual fear and increased fear to a neutral context upon repeated exposure.
Highlights
Hyperpolarization-activated cyclic nucleotide-gated channels are widely expressed in the brain and other parts of the central and peripheral nervous systems (Pape, 1996; Robinson and Siegelbaum, 2003; Biel et al, 2009)
The functional role of HCN1 and HCN2 channels have been extensively analyzed in the heart and the brain
Using the HCN3−/− mouse line, we have previously reported the role of HCN3 channels for late repolarization in action potential of ventricular cardiomyocytes (Fenske et al, 2011)
Summary
Hyperpolarization-activated cyclic nucleotide-gated channels are widely expressed in the brain and other parts of the central and peripheral nervous systems (Pape, 1996; Robinson and Siegelbaum, 2003; Biel et al, 2009). Ih has been shown to play a key role in the control of basic functions of neurons, including determination of resting membrane potential, dendritic integration, synaptic transmission, and action potential (AP) firing (Biel et al, 2009). These functions have been attributed almost exclusively to HCN1, HCN2, and HCN4 channels. Functional evidence in favor of a physiological role of HCN3 in vision is lacking so far
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