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

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.