Editors' ChoiceNeurology

Excited to Madness

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Science Translational Medicine  19 Jan 2011:
Vol. 3, Issue 66, pp. 66ec8
DOI: 10.1126/scitranslmed.3002125

Research into the pathophysiology of schizophrenia has implicated new pathways in addition to disruption of monoamine neurotransmitter function. Studies of certain psychomimetic substances in humans and animals suggest that disruption of excitatory signaling through glutamate receptors may be involved. Meanwhile, direct evidence from post-mortem histopathology studies of brain tissue from schizophrenia patients suggests that inhibitory processes that work through γ-aminobutyric acid, or GABA, receptors are also disrupted. Disturbances in excitatory and inhibitory pathways may be especially important in the prefrontal cortex, which is responsible for higher cognitive capacities such as language, planning, and abstract thought. But, do disturbances in excitatory signaling directly disrupt inhibitory processes in the prefrontal cortex? In their new study, Rotaru and colleagues set out to discover the answer.

These authors evaluated how prefrontal cortex neurons in the mouse brain responded electrically to excitatory signaling through a key glutamatergic receptor subtype, the N-methyl-D-aspartate (NMDA) receptor. NMDA receptor signaling is critical for learning and adaptive processes in the brain, and its disruption has been implicated in schizophrenia. The authors found that fast-spiking inhibitory GABAergic interneurons (which also have been implicated in schizophrenia) expressed fewer NMDA receptors (relative to another glutamatergic receptor subtype) and were less influenced by NMDA receptor signaling compared with excitatory (pyramidal) neurons. In addition, using a computational network model they found that activation of a non-NMDA glutamate receptor subtype (the AMPA receptor) was sufficient to elicit synchronous γ oscillations in pyramidal neurons. Altered oscillations may underlie the prefrontal cortex cognitive dysfunction that is characteristic of schizophrenia. Because these oscillations are highly dependent on GABAergic interneurons, the AMPA receptor effect suggests that oscillatory disturbances in schizophrenia do not result from altered NMDA receptor function. Taken together, these results indicate that one cannot simply attribute aberrant activity of inhibitory GABAergic interneurons to altered excitatory NMDA receptor signaling. This suggests that inhibitory GABAergic interneurons are a unique locus of disease pathogenesis and hence constitute a new target for therapeutic intervention. We await the development of a new class of drugs that will act on inhibitory GABAergic neurons in the prefrontal cortex in order to restore harmony to the schizophrenia brain.

D. C. Rotaru et al., Glutamate receptor subtypes mediating synaptic activation of prefrontal cortex neurons: Relevance for schizophrenia. J. Neuroscience 31, 142–156 (2011). [Abstract]

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