NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia - PubMed (original) (raw)

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NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia

Guillermo Gonzalez-Burgos et al. Schizophr Bull. 2012 Sep.

Abstract

Gamma oscillations appear to be dependent on inhibitory neurotransmission from parvalbumin (PV)-containing gamma-amino butyric acid neurons. Thus, the abnormalities in PV neurons found in schizophrenia may underlie the deficits of gamma-band synchrony in the illness. Because gamma-band synchrony is thought to be crucial for cognition, cognitive deficits in schizophrenia may reflect PV neuron dysfunction in cortical neural circuits. Interestingly, it has been suggested that PV alterations in schizophrenia are the consequence of a hypofunction of signaling through N-methyl-D-aspartate (NMDA) receptors (NMDARs). Here, we review recent findings that address the question of how NMDAR hypofunction might produce deficits of PV neuron-mediated inhibition in schizophrenia. We conclude that while dysregulation of NMDARs may play an important role in the pathophysiology of schizophrenia, additional research is required to determine the particular cell type(s) that mediate dysfunctional NMDAR signaling in the illness.

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Figures

Fig. 1.

Fig. 1.

Major subtypes of perisomatic-targeting gamma-amino butyric acid (GABA) neurons in cortical circuits. Both parvalbumin (PV)-positive and cholecystokinin (CCK)-positive basket cells (green and yellow, respectively) target the soma and proximal dendrites of the pyramidal cell membrane. PV-positive chandelier cells (red) target the axon initial segment. These 3 GABA neuron subtypes signal via GABAA receptors, although different GABAA receptor subtypes may mediate the response to GABA at each type of synapse (not shown in the scheme). As described in the main text, current data suggest that gamma oscillation production depends mostly on pyramidal neuron inhibition by PV-positive basket cells.

Fig. 2.

Fig. 2.

Two different circuit-based models for gamma oscillation production. In the Interneuron Network Gamma (ING) model (left panel), the oscillation depends on reciprocal inhibitory interactions between parvalbumin (PV)-positive basket cells. Some form of continuous (tonic) excitatory current is the main source of interneuron activation in ING. Important for the ING model are the electrical gap-junction connections (zig-zag wires) between PV-positive basket cells. In ING, pyramidal cells are synchronized rhythmically by the interneuron network but are not directly involved in rhythm production. In the Pyramidal Interneuron Network Gamma (PING) model (right panel), oscillations depend on the interplay between pyramidal cells and gamma-amino butyric acid neurons via recurrent synaptic connections. In PING models, interneurons are driven by the phasic (synaptic) excitatory glutamate–mediated currents arriving from the pyramidal cells, which are synchronized rhythmically by feedback inhibition. Monosynaptic excitation from pyramidal cells is the main source of interneuron activation in PING. Therefore, in PING, pyramidal cells are directly involved in the gamma rhythm mechanisms. As reviewed in the main text, some current data favor the PING over the ING model.

Fig. 3.

Fig. 3.

Properties of _N_-methyl-

d

-aspartate receptor (NMDAR)- and AMPAR-mediated excitatory synaptic currents (EPSCs). Various properties distinguishing NMDAR-EPSCs and AMPAR-EPSCs are described in the main text. Especially, important for models of gamma oscillations is the much shorter duration of the AMPAR-EPSC relative to the NMDAR-EPSC. Whereas short-lasting AMPAR-EPSCs are sufficient to support robust gamma oscillations, long-lasting NMDAR-EPSCs produce asynchronous and delayed postsynaptic interneuron firing that is not locked to the incoming inputs from pyramidal cells and in a PING model of gamma oscillations reduces gamma oscillation power. Such an inverse relation between gamma power and NMDAR contribution suggests that the reduction of NMDAR contribution at synapses onto parvalbumin (PV)-positive basket cells that occurs during normal postnatal development, helps optimize gamma oscillation production during cortical circuit development. Thus, during gamma oscillations in adult cortex, PV-positive basket cells appear to be mostly driven by fast AMPAR-mediated excitation. See main text for additional details.

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