Increased Size and Stability of CA1 and CA3 Place Fields in HCN1 Knockout Mice

Abstract

Summary Hippocampal CA1 and CA3 pyramidal neuron place cells encode the spatial location of an animal through localized firing patterns called “place fields”. To explore the mechanisms that control place cell firing and their relationship to spatial memory, we studied mice with enhanced spatial memory resulting from forebrain-specific knockout of the HCN1 hyperpolarization-activated cation channel. HCN1 is strongly expressed in CA1 neurons and entorhinal cortex grid cells, which provide spatial information to the hippocampus. Both CA1 and CA3 place fields were larger but more stable in the knockout mice, with the effect greater in CA1 than CA3. As HCN1 is only weakly expressed in CA3 place cells, their altered activity likely reflects loss of HCN1 in grid cells. The more pronounced changes in CA1 likely reflect the intrinsic contribution of HCN1. The enhanced place field stability may underlie the effect of HCN1 deletion to facilitate spatial learning and memory.

Grid scale drives the scale and long-term stability of place maps

“…Previous work demonstrated that germline knockout of forebrain HCN1 channels increased both grid and place scale 30, 31 . To selectively examine how grid scale impacts place coding and behavior, we regulated HCN1 channel expression specifically in the MEC by injecting Cre-expressing AAV (AAV-DJ CMV cre-GFP) into the MEC of adult floxed HCN1 knockout mice (iCre-KO) and their wildtype littermates (iWT) (Fig.…”

“…The mechanism underlying this observation likely lies in the fact that inputs from large grid scales are less likely to overlap in a way that would create a strong spatial signal, allowing other inputs to dominate the location of the place field. This relationship however, likely depends on the degree of plasticity associated with various inputs, as previous manipulations that expanded grid scale and enhanced hippocampal plasticity at synapses receiving MEC input resulted in increased long-term place stability 30, 31, 46 . Even so, as grid spacing in ventral MEC is at least five times wider than spacing in dorsal MEC 47 and a general dorsal to ventral topography exists in the projections from MEC to CA1 48 , our simulations thus predict that, in the normal animal, ventral place cells should show more remapping than dorsal place cells when non-spatial cues change.…”

“…To experimentally test the impact of grid scale on place cell coding and behavior we took advantage of the expansion in grid scale observed after the loss of HCN1 channels 29, 30 , which leaves grid periodicity and other functionally-defined MEC neurons intact. While previous work deleted HCN1 across the forebrain 29–31 , we used a viral approach to knockout HCN1 in the MEC of adult mice, allowing us to examine how grid scale controls place codes, navigation and memory.…”

Functional organization of the hippocampal longitudinal axis

“…The expression profiles of genes encoding adhesion molecules and ion channels 32,43 may determine intrinsic electrophysiological properties of discrete hippocampal neuronal populations, such as the differences in neuronal excitability 45 and synaptic plasticity [46][47] that have been detected along the long axis. For example, hyperpolarisation-activated cation channels HCN1 and HCN2, which mediate hyperpolarization-activated currents (I h ) currents, exhibit dorsoventral expression differences 48 and are important for a spatial function that is dorsoventrally graded [49][50][51] . In general, neurotransmitter receptor expression varies across the long axis for the majority of transmitter systems (Supplementary Table 1).…”

Advances in Understanding of Structure, Function and Plasticity of HCN Channels

“…HCN4 is vital for cardiac development; its knockout fails to have sinoatrial node-like action potential in mice and such knockouts are embryonic lethal [31][32][33] . HCN1 also regulates the size and stability of hippocampal place fields 34 . HCN1 knockdown results in enhancement of dorsal hippocampal activity, which manifests in states akin to anxiolytic-and antidepressantlike behaviours 35 , raising hopes of targeting HCN1 for treatment of depression in the future.…”