Role of HCN1 channels in the function and malfunction of parvalbumin positive interneurons

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Project Summary Recent clinical findings implicate de novo mutations in the gene encoding the hyperpolarization-activated HCN1 cation channel in severe forms of childhood epilepsy. At the same time genome-wide association studies demonstrate a strong link of the HCN1 locus with schizophrenia. Here we aim to provide a detailed characterization of the role of HCN1 in normal neural function, and to determine how disease-causing HCN1 mutations perturb neural activity to generate disordered brain function. HCN1 channels are unusual in that they are activated by membrane hyperpolarization, yet conduct an inward depolarizing Na+/K+ current, and show a contrasting pattern of subcellular localization in the distinct classes of neurons in which they are expressed. Thus, the channel is strongly expressed in hippocampal CA1 and neocortical layer 5 pyramidal neurons, where it is targeted to the apical dendrites in a striking gradient of increasing density with increasing distance from the soma. HCN1 is also strongly expressed in parvalbumin-positive inhibitory neurons (PV INs), where, in contrast to pyramidal neurons, it is targeted to PV IN axons and presynaptic terminals. Studies of mice with a general or forebrain-restricted genetic deletion of HCN1 have revealed the important role of this channel as a negative constraint of hippocampal pyramidal neuron dendritic integration and long-term synaptic plasticity, and of hippocampal-dependent spatial memory. Loss of HCN1 decreases the precision of pyramidal neuron place cell spatial coding while increasing the stability of spatial representations. In contrast to the well-studied role of HCN1 in pyramidal neuron function, relatively little is known about the role of HCN1 in inhibitory neurons. This lack of information prevents a full appreciation as to how HCN1 contributes to both normal brain function and disease, given the importance of inhibitory neurons, and PV INs in particular, in these processes. In addition, because HCN1 was deleted from both excitatory and inhibitory neurons in the HCN1 knockout mice examined to date, the extent to which the reported alterations in learning and memory and in vivo firing properties reflect the role of HCN1 in excitatory versus inhibitory neurons is unclear. In our application we propose to examine in detail how HCN1 contributes to PV IN function at the cellular, in vivo network, and behavioral levels. We will thus explore: the role of wild-type HCN1 in regulating PV IN intrinsic excitability and presynaptic function (Aim 1); how PV IN function is perturbed by epilepsy-associated HCN1 mutations (Aim 3a); how selective deletion of wild-type HCN1 from PV INs alters the in vivo coding of spatial information, as well as spatial and non-spatial memory behavior (Aim 2); and the paradoxical effects of certain anti-epileptic drugs to increase seizures in mice harboring epilepsy-associated HCN1 mutations (Aim 3b). Our goal in these studies is to both provide basic information about how a given channel expressed in a specific class of neurons contributes to brain function, and to provide new insights into disease mechanisms that may suggest new therapeutic approaches.