Regulation of prefrontal glutamate by the endogenous neuromodulator kynurenic acid as measured by rapid electrochemistry: relevance to schizophrenia

Schizophrenia is one of the most debilitating neuropsychiatric disorders, with a prevalence of approximately 1% worldwide. Symptoms include impairing deficits in cognitive processes (e.g., working memory, attention, and cognitive flexibility) which are currently elusive to treatment. Alpha-7 nicotinic acetylcholine receptors (α7 nAChRs) may be a critical link between the dysregulated cortical glutamatergic transmission and cognitive deficits in schizophrenia. Elevated levels of the endogenous, astrocyte-derived neuromodulator kynurenic acid (KYNA), a potent, non-competitive α7 nAChR antagonist, in the brains and cerebrospinal fluid (CSF) of schizophrenic patients suggests that KYNA binding may cause or exacerbate cortical dysregulation in schizophrenia. Thus, we used a state-of-the-art microelectrode array (MEA) to amperometrically examine the regulation of glutamate release by KYNA in the prefrontal cortex (PFC) of intact, freely moving rats. The MEA allows for the selective quantification of glutamate levels with second-by-second resolution (500-800 ms), a limit of detection of ≤0.5 μM, and outstanding spatial resolution (