Enhanced Learning in Channel Knockout

Abstract

Apparently, a single ion channel can have very different roles in learning and memory depending on the cell type in which it is expressed and the pattern of connectivity of those cells. Nolan et al . derive this conclusion from their studies of mice lacking the HCN1 protein, a subunit of a hyperpolarization-activated, cyclic nucleotide-gated, cation nonselective channel that accounts for hyperpolarization-activated inward currents ( I h ). HCN1 knockout mice have defective motor learning that appears to result from loss of function in Purkinje cells. However, the authors analyzed mice specifically lacking HCN1 in forebrain neurons and found that the animals actually performed better than wild-type animals in learning to accomplish a spatial memory task in which they have to use spatial cues to find a platform that is hidden under water. Loss of the channel also enhanced long-term memory of how to perform the task. In the CA1 region of the hippocampus, a brain area known to be important in spatial learning and memory, enhanced low-frequency oscillations in neuronal network activity were detected in the knockout animals. Single pyramidal cells of this region also showed greater response to low-frequency oscillatory currents when HCN1 was lacking. The pyramidal cells integrate inputs that come directly from the cerebral cortex (the perforant pathway) with hippocampal inputs from the Schaffer collateral pathway. HCN1 channels are more abundant in the distal dendrites where perforant pathway inputs are localized, and loss of HCN1 preferentially enhanced postsynaptic responses to a single input from the perforant pathway. Similarly, long-term potentiation was enhanced at these perforant path synapses. The authors propose that learning may be suppressed by HCN1 channels because they inhibit postsynaptic changes at distal dendrites that could otherwise result in synaptic plasticity. The loss of HCN1 changes the way in which pyramidal cells integrate incoming signals, enhancing response to low-frequency waveforms and also favoring response to the distal rather than proximal dendrites. This may be particularly important for spatial learning and memory because CA1 pyramidal neurons are thought to compare sensory input from the perforant pathway with stored information from the CA3 region. M. F. Nolan, G. Malleret, J. T. Dudman, D. L. Buhl, B. Santoro, E. Gibbs, S. Vronskaya, G. Buzsáki, S. A. Siegelbaum, E. R. Kandel, A. Morozov, A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons. Cell 119 , 719-732 (2004). [Online Journal]