Cellular mechanisms and function of hippocampal gamma oscillations

Gamma oscillations (30 - 120 Hz) are a common feature of active cortical networks and changes in these rhythms can act as a useful marker of circuit dysfunction in psychiatric disorders and neurological disease. While their function remains debated, there has been converging evidence regarding their mechanism of generation. These rhythms depend upon the spiking of inhibitory interneurons, which synchronise the firing of excitatory pyramidal cells via fast synaptic inhibition. Specifically, parvalbumin-expressing interneurons, which target the perisomatic domain of pyramidal neurons, are thought to play the key role in generating and maintaining gamma oscillations in the brain. However, it was recently demonstrated that somatostatin-expressing interneurons, which target the dendritic domains of pyramidal neurons, are responsible for the generation of lowfrequency gamma oscillations in the primary visual cortex of awake mice. It is not yet known if the involvement of somatostatin-expressing interneurons in gamma rhythmogenesis is specific to visually-induced oscillations in V1, or if it is general phenomenon that occurs across brain areas. Here, we took advantage of optogenetic techniques to test the involvement of parvalbumin- and somatostatinexpressing interneurons in a well studied model of carbachol-induced gamma oscillations in the hippocampal CA3 in vitro. For both classes of interneurons, we found that rhythmic photo-activation was sufficient to entrain ongoing gamma oscillations, and that the predominant effect of sustained photo-activation was to decrease the power and increase the frequency of gamma oscillations. Importantly, there was a functional distinction between the interneuronal classes. While photoinhibition of parvalbumin-expressing interneurons decreased the oscillation power, photo-inhibition of somatostatin-expressing interneurons both decreased the oscillation power and increased its frequency. These experiments suggest that the activity of both interneuron classes are important for carbachol-induced oscillations in hippocampal area CA3. They also indicate that somatostatin-expressing interneurons may have a more intimate role in the control of gamma oscillation frequency. Interestingly, sustained photo-activation of somatostatin-expressing interneurons was suficient to induce de novo high-frequency gamma oscillations. Our experiments reveal that the de novo gamma oscillations may have different properties than cchinduced oscillations, but may also depend on synaptic excitation.
Our data suggest that several different interneuronal subtypes may be necessary to generate and/or maintain oscillations across the gamma range, but are also consistent with the idea that rhythmic perisomatic inhibition is a critical feature of low-frequency gamma oscillations in the hippocampus. In order to further understand the function of rhythmic perisomatic inhibition, we used dynamic clamp to inject inhibitory conductance trains into pyramidal neurons, and examined the effects of disturbing rhythmicity and/or synchrony on pyramidal cell spiking. Previous evidence using this approach has highlighted a role for gamma frequency synchronisation of excitatory inputs in multiplicative gain enhancement of principal cell output. Here, we show that rhythmic inhibition can also induce multiplicative increases in the gain of principal cell output. Moreover, we found that reductions in either rhythmicity or synchrony of the input trains impaired that multiplicative gain enhancement in principal cells. These experiments suggest that inputs at gamma frequency are ideally suited for multiplicatively enhancing gain, and highlight an important implication for gamma oscillations at the single cell level.
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Advisor: Mann, E