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. 2011 Dec 7;31(49):18137-48.
doi: 10.1523/JNEUROSCI.3041-11.2011.

Downregulation of parvalbumin at cortical GABA synapses reduces network gamma oscillatory activity

Vladislav Volman  1 , M Margarita Behrens, Terrence J Sejnowski
Affiliations

Downregulation of parvalbumin at cortical GABA synapses reduces network gamma oscillatory activity

Vladislav Volman et al. J Neurosci. .

Abstract

Postmortem and functional imaging studies of patients with psychiatric disorders, including schizophrenia, are consistent with a dysfunction of interneurons leading to compromised inhibitory control of network activity. Parvalbumin (PV)-expressing, fast-spiking interneurons interacting with pyramidal neurons generate cortical gamma oscillations (30-80 Hz) that synchronize cortical activity during cognitive processing. In postmortem studies of schizophrenia patients, these interneurons show reduced PV and glutamic acid decarboxylase 67 (GAD67), an enzyme that synthesizes GABA, but the consequences of this downregulation are unclear. We developed a biophysically realistic and detailed computational model of a cortical circuit including asynchronous release from GABAergic interneurons to investigate how reductions in PV and GABA affect gamma oscillations induced by sensory stimuli. Networks with reduced GABA were disinhibited and had altered gamma oscillations in response to stimulation; PV-deficient GABA synapses had increased asynchronous release of GABA, which decreased the level of excitation and reduced gamma-band activity. Combined reductions of PV and GABA resulted in a diminished gamma-band oscillatory activity in response to stimuli, similar to that observed in schizophrenia patients. Our results suggest a mechanism by which reduced GAD67 and PV in fast-spiking interneurons may contribute to cortical dysfunction in schizophrenia and related psychiatric disorders.

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Figures

Figure 1.
Figure 1.
Properties of gamma oscillations in cortical network model. A1, Raster plot of network dynamics (IN neurons are 1–180). A2, A3, Membrane potentials of sample PY and IN neurons. A4, Local field potential (computed as average over membrane potentials of all neurons). B1, B2, Distributions of firing rates for PY (B1) and IN (B2) neurons. C, Spectrogram (time-frequency) of network LFP. D, Time-averaged distribution of spectral power from C. For all plots, network stimulation frequency was vSTIM = 250 Hz.
Figure 2.
Figure 2.
Gamma oscillations are modulated by synaptic coupling between PY and IN populations. A1, Raster plot of network dynamics for scenario in which PY-to-IN synaptic coupling was reduced to 60% of its value in the baseline model (Fig. 1A). A2, Time-averaged distribution of spectral power of this model (red) and the baseline model (black). Insets show the dependence of location (top) and magnitude (bottom) of power peak on the relative strength of PY-to-IN coupling. Closed black and red circles are for the corresponding scenarios shown in the main plot. B1, B2, Raster plot (B1) and spectral characterization (B2) of network dynamics for scenario in which IN-to-PY coupling was varied. Interpretation of data follows that shown in A. C1, C2, Raster plot (C1) and spectral characterization (C2) of network dynamics for scenario in which GABA recovery time was varied. Interpretation of data follows that shown in A. D1, D2, Raster plot (D1) and spectral characterization (D2) of network dynamics for scenario in which strength of per spike synaptic response was varied. Interpretation of data follows that shown in A. For A–D, the network stimulation frequency was vSTIM = 250 Hz.
Figure 3.
Figure 3.
Deficit in parvalbumin impairs gamma-band activity through asynchronous GABA release. A, Examples of synaptic response (Y) for different concentrations of parvalbumin at model synapses: the baseline model with [PV] = 100 μm (A1); [PV] = 10 μm (A2); [PV] = 0 μm (A3). Synapses were stimulated by seven spikes at 40 Hz. To facilitate presentation of asynchronous release, the phasic part of synaptic response was truncated. B, Characterization of activity in the neuron deficit model. B1, Spectral power plots of baseline model (F[PV] = 0 = 0, black) versus the F[PV] = 0 = 0.4 model (red). B2, Magnitude (blue circles) and location (green circles) of spectral power peak versus the fraction of IN neurons with zero PV. Black and red points correspond to those shown in left plot. B3, Rates of PY (black) and IN (red) neurons firing versus the F[PV] = 0. C, Characterization of activity in concentration deficit model. C1, Spectral power plots of baseline model ([PV] = 100 μm, black) versus the [PV] = 40 μm model (red). C2, Magnitude and location of spectral power peak versus the PV concentration. C3, Rates of PY (black) and IN (red) neurons firing versus the PV concentration.
Figure 4.
Figure 4.
PV deficiency at GABA synapses prevents the disinhibition of network dynamics. A, Representative membrane potentials and LFPs obtained for scenarios of intact networks (F[PV] = 0 = 0), in which all model interneurons were subject to hyperpolarizing DC current IHYP. A1–A3, Membrane potential of sample interneuron (A1), membrane potential of sample pyramidal neuron (A2), and local field potential (A3) for the case IHYP = 0 μA/cm2. B, The same as in A, but for IHYP = 3 μA/cm2. C, Network-averaged firing rates of model PY (black squares) and IN (gray circles) neurons versus the magnitude of IHYP. Data points are averages ± SEM. D, Magnitude of spectral power peak versus the magnitude of IHYP. E, Location of spectral power peak versus the magnitude of IHYP.
Figure 5.
Figure 5.
Parvalbumin deficit causes reduced response to stimuli. A1, A2, Spectrograms (time frequency) of network LFP, for baseline scenario (A1) and scenario with PV deficiency (F[PV] = 0 = 0.4, A2). In both cases, stimulus was presented at T = 2 s (arrow) and lasted for 40 ms. Stimulus rate was 400 Hz. B1, Spectral response averaged over time duration of stimulus presentation for baseline (black) versus the PV-deficient (red) models. B2, Spectral response averaged over time duration of 200 ms after stimulus cessation for baseline (black) versus PV-deficient (red) models. Stimulus rate was 400 Hz. C1, Magnitude of spectral power peak (time average over stimulus duration) versus F[PV] = 0 and relative (to the baseline stimulation of v0 = 150 Hz) increase in stimulation rate. C2, Firing rates of PY (black) and IN (red) model neurons during the 40 ms stimulus, in baseline (solid line) versus the F[PV] = 0 = 0.4 model (dashed line). D1, Magnitude of spectral power peak (time average over 200 ms after stimulus) versus F[PV] = 0 and relative (to the baseline stimulation of v0 = 150 Hz) increase in stimulation rate. D2, Firing rates of PY (black) and IN (red) model neurons in the time window of 200 ms after the stimulus, in baseline (solid line) versus the F[PV] = 0 = 0.4 model (dashed line).
Figure 6.
Figure 6.
Reduced GAD67 exacerbates the effect of parvalbumin deficit on network activity. A1, Spectral power plots for the scenario in which PV deficit is accompanied by reduced GABA conductance: gGABA at 100% of its baseline value and [PV] = 100 μm (solid black); gGABA at 100% of its baseline value and [PV] = 40 μm (dashed black); gGABA at 60% of its baseline value and [PV] = 100 μm (solid red); gGABA at 60% of its baseline value and [PV] = 40 μm (dashed red). A2, A3, Quantification of spectral peak power (A2) and frequency (A3) changes versus different PV concentrations and alterations in GABA conductance. Black squares, gGABA at 100% of its baseline value. Red triangles, gGABA at 60% of its baseline value. Network stimulation frequency was vSTIM = 250 Hz. B1, Spectral power plots for the scenario in which PV deficit is accompanied by slower time τR of GABA synapse recovery from depression: τR = 0.2 s and [PV] = 100 μm (solid black); τR = 0.2 s and [PV] = 40 μm (dashed black); τR = 0.4 s and [PV] = 100 μm (solid red); τR = 0.4 s and [PV] = 40 μm (dashed red). B2, B3, Quantification of spectral peak power (B2) and frequency (B3) changes versus different PV concentrations and altered time of GABA synapse recovery from depression. Black squares, τR = 0.2 s. Red triangles, τR = 0.4 s. Network stimulation frequency was vSTIM = 250 Hz. C1–C4, Firing rates of PY (C1, C3) and IN (C2, C4) model neurons for different scenarios shown in A and B. D1, Magnitude of spectral power peak (time average over stimulus duration) versus F[PV] = 0 and relative (to the baseline stimulation of v0 = 150 Hz) increase in stimulation rate. D2, Magnitude of spectral power peak (time average over 200 ms after stimulus) versus F[PV] = 0 and relative increase in stimulation rate. Color scale is the same for D1–D2. E1, Spectral power over the time duration of stimulus presentation (40 ms) for different scenarios: gGABA at 100% of its baseline value and F[PV] = 0 = 0 (solid black); gGABA at 100% of its baseline value and F[PV] = 0 = 0.4 (dashed black); gGABA at 60% of its baseline value and F[PV] = 0 (solid red); gGABA at 60% of its baseline value and F[PV] = 0 = 0.4 (dashed red). E2, Spectral power over 200 ms following stimulus cessation; keys are the same as in E1. In both E1 and E2, stimulus rate was vSTIM = 400 Hz.
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