08, df = 69) in knockout mice (percent area = 29% ± 2.5%) compared to control mice (22.9% ± 1.3%). Similarly in the track, CA3 place fields were 22.9% larger (p = 0.033, t = 2.19, df = 47) in knockout mice (percent area = 33.7% ± 2.35%) compared to control mice (27.4% ± 1.55%; Figure 3B, right). Given the small contribution of HCN1 to CA3 neuron properties, the difference in place field size in the CA3 region of knockout compared to control mice is likely attributable to a change in input from the entorhinal cortex, where HCN1 deletion leads to an increase in grid field size and spacing Anticancer Compound Library manufacturer (Giocomo et al., 2011). By contrast the finding

that the change in place field size is about twice as great in CA1 versus

CA3, (box: p = 0.043, t = 2.04, df = 152; track: p = 0.037, t = 2.10, df = 117), likely reflects the difference in expression levels of HCN1 in these regions. We did not find any significant difference between peak firing rates of place cells in control mice (Figures 1A, 1B, 2A, and 2B) versus knockout mice (Figures Roxadustat mw 1C, 1D, 2C, and 2D). This is also evident from four representative 3D plots (Figure 1 and Figure 2) from each group of mice in CA1 and CA3 regions. HCN1 is also expressed in inhibitory basket cell interneurons in the hippocampus (Aponte et al., 2006). We therefore examined whether interneurons play a role in regulating place field size. Properties of interneurons cannot be analyzed by the approach used to characterize second place cell firing, as the interneurons do not have well defined firing rate peaks or complex spike bursts. Hence we looked at the spike-timing of interneurons and place cells in both CA1 and CA3. We analyzed the intrinsic spike frequencies

of theta modulated place cells and interneurons of CT and KO mice by calculating the spike-time autocorrelation histogram. It has been well established in previous studies that the intrinsic spike frequencies of a cell become slower if place fields expand and faster if place fields shrink (Maurer et al., 2005). The intrinsic spike frequencies of pyramidal neuron place cells were slower in KO mice compared to CT mice in both CA1 (p = 0.006, t = 2.78, df = 155) and CA3 (p = 0.034, t = 2.14, df = 118) regions of hippocampus, consistent with the larger place fields in the KO mice. In contrast, there was no change in intrinsic spike frequencies of CT and KO interneurons in either CA1 or CA3 regions (Figure S3). This indicates that changes in interneuron firing may not contribute to the change in place field size observed in the HCN1 KO mice. The increase in place field size upon HCN1 deletion is somewhat surprising given the enhanced spatial learning and memory observed in the KO mice (Nolan et al., 2004). We therefore examined the influence of HCN1 on stability of the place fields by comparing the place fields from session 1 with those recorded 24 hr later during session 2.