Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks

Abstract

Networks of GABAergic interneurons are of critical importance for the generation of gamma frequency oscillations in the brain. To examine the underlying synaptic mechanisms, we made paired recordings from "basket cells" (BCs) in different subfields of hippocampal slices, using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the parvalbumin promoter. Unitary inhibitory postsynaptic currents (IPSCs) showed large amplitude and fast time course with mean amplitude-weighted decay time constants of 2.5, 1.2, and 1.8 ms in the dentate gyrus, and the cornu ammonis area 3 (CA3) and 1 (CA1), respectively (33-34 degrees C). The decay of unitary IPSCs at BC-BC synapses was significantly faster than that at BC-principal cell synapses, indicating target cell-specific differences in IPSC kinetics. In addition, electrical coupling was found in a subset of BC-BC pairs. To examine whether an interneuron network with fast inhibitory synapses can act as a gamma frequency oscillator, we developed an interneuron network model based on experimentally determined properties. In comparison to previous interneuron network models, our model was able to generate oscillatory activity with higher coherence over a broad range of frequencies (20-110 Hz). In this model, high coherence and flexibility in frequency control emerge from the combination of synaptic properties, network structure, and electrical coupling.

Figure 1

Identification of parvalbumin-expressing BCs in slices of transgenic mice. (A) EGFP labeling, (B) parvalbumin immunoreactivity probed with anti-parvalbumin antibody and Cy3-conjugated secondary antibody, and (C) biocytin labeling with AMCA-conjugated avidin. Images were taken from the same cell in the CA1 pyramidal cell layer (arrowheads). (D) Light-microscopic image of a biocytin-labeled interneuron (EGFP-positive) in the CA3 region visualized using DAB as a chromogen. Note axonal arborization in the pyramidal cell layer.

Figure 2

Fast chemical and electrical transmission at BC–BC synapses in the hippocampus. (A) Unitary IPSCs in a pair of EGFP-labeled BCs (Left) and a pair of an EGFP-positive BC and an EGFP-negative principal cell (Right) in the CA1 subfield. Presynaptic action potentials are shown on top, unitary IPSCs (seven each) are shown superimposed in the center, and average unitary IPSCs (from 20 sweeps) are depicted below. Unitary IPSCs were almost completely blocked by the GABA_A receptor antagonist bicuculline methiodide (20 μM; Bottom traces). Note difference in the IPSC decay time constant between the two synapses. (B) PPD of unitary IPSCs in a pair of EGFP-labeled BCs (Left) and a pair of an EGFP-positive BC and an EGFP-negative principal cell (Right) in the CA1 subfield. Action potentials with a 50-ms interpulse interval are shown on top, corresponding average IPSCs (from 30 sweeps) are depicted at the bottom. Note similarity of PPD between the two synapses. Same pairs as those shown in A. (C and D) Electrical coupling in a pair of EGFP-labeled neurons in the DG. In C, the presynaptic cell was held in current-clamp, and the postsynaptic cell was held in voltage-clamp configuration. Lower traces are averages from 31 sweeps. Note that electrical PSCs mirrored presynaptic action potentials. In D, both cells were held in the current-clamp mode, and long de- or hyperpolarizing current pulses were applied. Traces are averages from 15 sweeps. The coupling ratio determined from pre- and postsynaptic voltage changes was 0.2.

Figure 3

A “realistic” interneuron network model with fast inhibitory synapses generates coherent activity over the entire gamma frequency range. (A and B) Network activity with standard parameters and unitary postsynaptic peak conductance g_GABA = 0.025 mS⋅cm⁻². Upper graphs are raster plots, with time on the horizontal axis, and index of the neuron in the network on the vertical axis. Each point represents an action potential. Lower graphs in A and B represent spike frequency histograms for the network; bin width 1 ms. (C and D) Analysis of inhibitory conductances during oscillations. Upper graphs represent the normalized total inhibitory conductance in a single interneuron (cell #1, G/g_GABA). The half-duration of the compound conductance changes determined from the last five oscillation cycles was 6.3 ms (C) and 8.1 ms (D), substantially slower than that of the unitary inhibitory conductance (1.4 ms). Lower graphs represent the synaptic output of the interneuron network simulated in a model principal neuron receiving convergent input from all interneurons [synaptic latency, 0.6 ms; decay time constants of unitary conductance, 1.2 ms (60% amplitude contribution) and 7.3 ms (40%), which was the typical inhibitory synaptic conductance change at BC–principal neuron synapses in CA1; see Table 1]. Tonic excitatory drive was applied at random time points −150 ms ≤ t < −100 ms, and chemical and electrical synapses were enabled at t ≥ 0 (type 1 simulation).

Figure 4

Parameters that determine coherence and frequency in the interneuron network model. All graphs show coherence (κ) plotted against the amplitude of the unitary postsynaptic peak conductance (g_GABA) and excitatory drive (I_μ). Action potential frequency in the network is shown by superimposed color code (see scale bar at bottom). (A) Simulations with standard settings. Chemical and electrical synapses; biexponential synaptic conductance with decay time constants of 1.2 ms (90% amplitude contribution) and 8 ms (10%); 50 μm spacing; gap junction conductance 0.01 mS⋅cm⁻². (B) Influence of the decay kinetics of the inhibitory postsynaptic conductance. (Left) Fast monoexponential decay (decay time constant 1.2 ms). (Right) Slow monoexponential decay (decay time constant 8 ms). (C) Effects of spacing of neurons. (Left) Decrease in cell-cell distance by a factor of 2 (25 μm). (Right) Increase by a factor of 1.5 (75 μm). (D) Impact of electrical synapses. (Left) Increased gap junction conductance (0.02 mS⋅cm⁻²). (Right) Block of gap junctions. In all simulations (A–D) step-like driving currents were applied to individual neurons with randomized onset times of −150 ms ≤ t < −100 ms. Chemical and electrical synapses were inactive at −150 ms ≤ t < 0 and enabled for t ≥ 0 (type 1 simulation). Coherence was calculated for the time interval 400 ≤ t < 500 ms. (E) Effects of synchronous application of drive to the entire network (Left) or to a subset of 20 adjacent cells (10% of the population; Right). Chemical and electrical synapses were enabled throughout the simulation, and a step-like excitatory drive was applied simultaneously to all or a subset of cells at t = 0 (type 2 simulation). Coherence was calculated for the time interval 0 ≤ t < 100 ms.