Networks of interneurons with fast and slow γ-aminobutyric acid type A (GABA _A ) kinetics provide substrate for mixed gamma-theta rhythm

TLDR

During active exploration, hippocampal neurons display nested theta (~8 Hz) and gamma (~40 Hz) rhythms, with gamma generated by fast GABA A interneuron interactions and theta traditionally viewed as extrinsic, yet slow GABA A synapses and their interneurons may locally contribute to theta and interact with fast interneurons. The study investigates how distinct fast and slow GABA A interneuron classes influence hippocampal rhythmicity. Biophysically based simulations model networks with separate fast and slow GABA A synaptic kinetics to explore these effects. Simulations demonstrate that such networks can produce mixed theta‑gamma rhythms under specific connectivity and homogeneity conditions, and that slow synapses are essential for amplifying and resynchronizing phasic responses to weak theta‑frequency drive even with heterogeneity.

Abstract

During active exploration, hippocampal neurons exhibit nested rhythmic activity at theta (≈8 Hz) and gamma (≈40 Hz) frequencies. Gamma rhythms may be generated locally by interactions within a class of interneurons mediating fast GABA A (GABA A,fast ) inhibitory postsynaptic currents (IPSCs), whereas theta rhythms traditionally are thought to be imposed extrinsically. However, the hippocampus contains slow biophysical mechanisms that may contribute to the theta rhythm, either as a resonance activated by extrinsic input or as a purely local phenomenon. For example, region CA1 of the hippocampus contains a slower class of GABA A (GABA A,slow ) synapses, believed to be generated by a distinct group of interneurons. Recent evidence indicates that these GABA A,slow interneurons project to the GABA A,fast interneurons that contribute to hippocampal gamma rhythms. Here, we use biophysically based simulations to explore the possible ramifications of interneuronal circuits containing separate classes of GABA A,fast and GABA A,slow interneurons. Simulated interneuronal networks with fast and slow synaptic kinetics can generate mixed theta-gamma rhythmicity under restricted conditions, including strong connections among each population, weaker connections between the two populations, and homogeneity of cellular properties and drive. Under a broader range of conditions, including heterogeneity, the networks can amplify and resynchronize phasic responses to weak phase-dispersed external drive at theta frequencies to either GABA A,slow or GABA A,fast cells. GABA A,slow synapses are necessary for this process of amplification and resynchronization.