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Inhibition of NMDA or GABA-A receptors but not reduction of GAD activity in the prefrontal cortex impairs preparatory attention

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Pehrson, A., Totah, N., & Moghaddam, B. (2009). Inhibition of NMDA or GABA-A receptors but not reduction of GAD activity in the prefrontal cortex impairs preparatory attention. Poster presented at 39th Annual Meeting of the Society for Neuroscience (Neuroscience 2009), Chicago, IL, USA.

Cite as: http://hdl.handle.net/21.11116/0000-0002-11C8-9
Schizophrenia is associated with cognitive dysfunction, including deficits in attention. The severity of cognitive deficits may be the best predictor of functional outcome among this patient population. Postmortem studies have reported altered cortical GABA neurotransmission in schizophrenia. For example, in the dorsolateral prefrontal cortex and anterior cingulate cortex (ACC), there is reduced density of GABA neurons, reduced expression of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD), and increased expression of the GABAA receptor. GABA interneurons in the prefrontal cortex are critical for proper functioning of this region and therefore most recent theories on cognitive deficits incorporate GABA deficiency in the microcircuits that subserve these deficits. Among these, two leading theories are that: 1) reduced GABA activity is an indirect consequence of NMDA deficiency whereby reduced NMDA-mediated glutamatergic drive of these neurons lowers their normal activity during task relevant events, and 2) reduced GAD expression is a primary pathology in schizophrenia leading to reduced GABA availability. One concern with the latter theory is that GABA availability is governed by the GABA shunt, which serves not only to produce GABA, but also to conserve the available supply. Thus, it may be the case that reduced GAD expression in schizophrenia is a compensatory mechanism that is not coupled with reductions in GABA availability, and may have little effect on cognition. In this study, we compared the effect of GAD inhibition with that of NMDA and GABA-A receptor inhibition in the ACC on performance of an attention task (3 choice serial reaction time task - 3CSRT) that is dependent on the ACC. This task requires a rat to attend to an array of three nose poke holes until a short (300ms) cue is lit in one of the holes, and then to poke in that hole to obtain a reward. Drugs were given either systemically or micro-injected into the ACC and included the GAD inhibitor 3-mercaptopropionic acid (3MPA), the GABAA antagonist SR95531, and the NMDA antagonist MK801. We find that that systemic 3MPA does not significantly affect 3CSRT performance at sub seizure-mimetic doses. Microinjection of 3MPA into the ACC at concentrations of 1-10 mM also fails to impair performance. In contrast, local injection of SR95531 impaired 3CSRT performance in a dose-dependent manner. Consistent with previous findings, NMDA receptor inhibition also affected performance. Collectively these findings suggest that while inhibition of GABA-A and NMDA receptors impair a cognitive function that is relevant to schizophrenia, inhibition of GAD, at least transiently, does not.