Molecular determinants of hippocampal oscillatory activity

In vitro electrophysiological studies in genetically modified mice with a deletion of the GluR-A subunit in parvalbumin-positive GABAergic interneurons (PV-GluR-A KO mice) provided evidence for the involvement of this cell-population in the generation of hippocampal network synchrony. Besides, these mice displayed several alterations in hippocampus-dependent cognitive tasks (Fuchs et al., 2007). To study the characteristics of hippocampal network synchrony thoroughly, we applied in vivo electrophysiological measurements in freely moving animals. We used tetrode and silicon probe hippocampal recordings from mutant and wildtype (WT) animals and compared cellular activity obtained from pyramidal cells and interneurons as well as network activity. The results can be summarized as follows: 1. PV-GluR-A KO mice exhibited increased ripple-power compared to WT mice. The underlying mechanism cannot be accounted for by an augmented cellular activity during ripples but by an increased phase-modulation of both pyramidal cells and interneurons as indicated by the unitary analysis. 2. The decreased gamma-power in the PV-GluR-A KO mice revealed by in vitro measurements could not be corroborated by the in vivo study. However, a reduction in gamma-frequency could be identified during REM-sleep of the PV-GluR-A KO mice. The phase-preference of pyramidal cells during gamma-oscillations was not different between genotypes. However, there was a delay of the phase-preference of interneurons in PV-GluR-A KO compared with WT mice. 3. The firing rate of pyramidal cells during theta-oscillations was decreased in PV-GluR-A KO mice whereas that of interneurons did not change significantly. We propose that the pyramidal cells’ underperformance is due to the altered function of interneurons. 4. Pyramidal cells were more “bursty” in PV-GluR-A mutants. The increased “burstiness” occurred during theta-, gamma- and ripple-oscillations. We think that the suboptimal work of interneurons makes pyramidal cell firing less “predictable” and maybe temporary fluctuations in the excitatory and inhibitory network state can disturb the optimal modes of pyramidal cell-discharge. In summary, this in vivo study provides direct evidence that PV-positive GABAergic interneurons play a crucial role in the generation of synchronous network activity in the hippocampus