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Claudia Racca"NMDA receptors modulation of cortical rhythms "

Abstract :


Psychiatric illnesses, particularly schizophrenia, are associated with changes in markers for interneurons (e.g. parvalbumin), which are specific classes of inhibitory nerve cells involved in the local modulation of activity within the various brain regions. Specifically, deficits in the interneuron marker parvalbumin are particularly prevalent in certain brain regions such as prefrontal cortex and medial temporal structures (e.g. entorhinal cortex and hippocampus). These interneurons, which appear to be mostly affected in schizophrenia, play a critical role in generating cortical rhythms in the electroencephalogram gamma-frequency band (30-60 Hz) - an oscillation associated with sensory processing and short term memory.
We investigated a possible link between the reduction in parvalbumin expression in GABAergic interneurons and the decrease in power of gamma frequency oscillations in the entorhinal cortex and hippocampal areas using genetic and acute animal models of schizophrenia-like illness. Our study demonstrated a layer-specific decrease in a gamma frequency rhythmic network activity in the entorhinal cortex, but not hippocampus. This suggested that a loss, or reduction in function of a fundamental class of inhibitory GABAergic interneurons, containing the calcium-binding protein parvalbumin and having a large expression of NMDA subtype of glutamate receptors, may underlie the dysfunction seen at the level of network oscillations, which are also observed in patients affected by schizophrenia. Our data also demonstrated how disruption of GABAergic interneuron function by NMDA receptor antagonists can affect gamma frequency oscillations in entorhinal cortex, but not hippocampus and, thereby, compromise cognitive functions.
The convergence of both genetic and acute models, exhibiting schizophrenia-like phenomena, on affecting local inhibition in the entorhinal cortex may, ultimately, result in cognitive deficits. Thus, cognitive impairment in schizophrenia may reflect abnormal inhibitory function, which could compromise the generation/maintenance of brain rhythms so important for many brain functions (e.g. theprocessing and integration of sensory and motor information). If these go wrong and the networks are not communicating normally, mental health conditions appear. Consequently, it is essential we understand how different neurons work together to produce these complex patterns of rhythmic activity. In particular, to identify the nature and function of the NMDA receptors expressed in parvalbumin-containing GABAergic interneurons in entorhinal cortex, and how they differ from those in the hippocampus in both normal conditions and models of schizophrenia.
The knowledge gained from these studies will be essential for the future design and development of new therapeutic approaches and agents to treat schizophrenia, such as new drugs related to specific NMDA receptor subtypes and NMDA receptor-related molecules, and their signalling pathways. Clinically enhancing NMDA receptor activity may be a powerful new strategy to improve the cognitive deficits in schizophrenic patients, an approach currently being pursued by pharmaceutical companies. The cognitive deficits seen in schizophrenia precede the emergence of psychopathology, often correlating with the severity of illness, thus restoring normal NMDA receptor function early in the disease might, in the long-term, be a means to prevent the establishment of the full psychotic syndrome.

Selected publications

Driver JE, Racca C, Cunningham MO, Towers SK, Davies CH, Whittington MA, LeBeau FE.
Impairment of hippocampal gamma-frequency oscillations in vitro in mice overexpressing human amyloid precursor protein (APP).
Eur J Neurosci. 2007 Sep;26(5):1280-8.

Nathalie Sans