We here ask: What is the consequence of HCN1 deletion www.selleckchem.com/products/chir-99021-ct99021-hcl.html for hippocampal place cell firing and place field properties? Do any changes evident in the hippocampus reflect changes in the EC inputs to hippocampus, or are they a result of changes intrinsic to the CA1 or CA3 place cells? We find changes in CA1 and CA3 place cell properties consistent with the observed changes in the EC grid cell

inputs to hippocampus. In addition, we observe a significantly greater change in the response properties of the CA1 neurons consistent with an intrinsic change in CA1 pyramidal cell firing and synaptic plasticity. These results demonstrate how alterations in encoding of the spatial environment by the EC and its transformation in the hippocampus may contribute to changes in long-term spatial memory.

Moreover, these results suggest the interesting possibility that the fine accuracy of spatial encoding and spatial memory storage may be separable. We obtained extracellular recordings using multiple tetrodes and compared firing properties of hippocampal CA1 and CA3 pyramidal neurons in forebrain-restricted HCN1 knockout mice (KO) to those in control littermates (CT) (Nolan et al., 2003 and Nolan et al., 2004). We focused on these two populations of hippocampal neurons because the CA3 neurons express HCN1 weakly KU-55933 ic50 (Santoro et al., 2000) and therefore should not be affected directly by the knockout, whereas the CA1 neurons strongly express HCN1 channels, which normally constrain the ability of the direct layer Florfenicol III EC inputs to excite CA1 neurons. Before examining place cell properties in vivo, we first directly examined the influence of HCN1 in CA3 neurons in acute hippocampal slices, which has not been previously characterized. Whole-cell current clamp recordings indicate that HCN1 plays little direct role in regulating CA3 electrophysiological properties, consistent with previous voltage-clamp results showing that CA3 neurons had little Ih (Santoro et al., 2000). Because of

potential voltage clamp artifacts in slice patch clamp recordings, we assayed Ih in CA3 neurons under current clamp conditions by measuring the voltage sag in response to a hyperpolarizing current injection, a characteristic property of the activation of Ih. In contrast to the large sag in CA1 neurons, the sag in control CA3 neurons was minute, with a sag ratio of only 0.99 (see Experimental Procedures), compared to a typical sag ratio of 0.7 in CA1 (Chevaleyre and Siegelbaum, 2010). The small sag in CA3 neurons was abolished in the KO mice (CT = 0.988 ± 0.001, n = 14; KO = 1.002 ± 0.001, n = 15, p < 0.001). Consistent with a minor role for HCN1 in CA3, HCN1 deletion caused no significant change in CA3 pyramidal neuron resting potential (CT = −73.6 ± 0.8 mV; KO = −73.3 ± 1.4 mV; p = 0.820), input resistance (CT = 133.2 ± 11.3 MΩ; KO = 129.7 ± 9.7 MΩ, p = 0.818), membrane time constant (CT = 21.0 ± 1.1 ms, KO = 21.6 ± 1.8 ms, p = 0.