Problem solving and other higher cognitive functions depend on working memory, a short-term memory typically lasting seconds, which is required to maintain and organize an active representation. Studies of learning and memory have tended to focus on the importance of long-term synaptic plasticity for long-term memory storage. Much less is known about how a neuron's non-synaptic integrative properties and excitability influence its ability to modify or translate synaptic changes into an output that can influence behavior. Similarly, relatively little is know about the cellular and molecular mechanisms of short-term explicit memory processes especially working memory. Such an understanding is not only important for the biology of memory storage, but is of great clinical importance as the organization of working memory processes is impaired in many psychiatric diseases, for example it is disordered in schizophrenia and in attention deficit disorders. Here we propose to investigate the cellular mechanisms of short-term explicit memory. We will focus on the role of neuronal integration and excitability and probe them by perturbing neuronal function in the prefrontal cortex and the hippocampus using restricted deletion of the gene encoding the HCN1 (hyperpolarization-activated cyclic nucleotide-gated, non-selective cation) channel. To achieve this aim, we will address three specific questions: 1) Does HCN1 modulate explicit short-term memory processes? 2) How does HCN1 knockout affect the physiological properties of circuits involved in short-term memory both in the prefrontal cortex? 3) Does HCN1 influence the 'on-line'neural representation of information during working memory?
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