Second-by-second measurement of stimulated glutamate release and its modulation by α7 and mGlu 2/3 receptors: relevance to schizophrenia

Dysregulation of cortical glutamatergic transmission is believed to contribute to the etiology of schizophrenia [1]. This position is supported by the psychotomimetic properties of NMDA antagonists such as phencyclidine (PCP) or ketamine in psychiatric and non-psychiatric populations [2,3]. Studies in animals reveal that these drugs decrease NMDA-mediated transmission [4], increase cortical glutamate release [5], and, as a result, inappropriately enhance AMPA-mediated transmission. Moreover, acute and subchronic administration of PCP produces cognitive deficits (e.g. working memory, cognitive flexibility, sensory-gating) that are present in schizophrenia [6]. Recently, animal models have been developed to determine the effects of various drugs on the restoration of glutamate transmission in prefrontal cortex (PFC) [7]. These studies have typically utilized microdialysis and/or electrophysiological measures to study aberrant glutamatergic transmission following the psychotomimetic PCP [1]. The two methods exhibit relative strengths and weaknesses in this regard. The identity of the molecules being measured can be identified with confidence using microdialysis and HPLC although the temporal (minutes) and spatial (0.5 to several mm) resolution is rather limited. Temporal resolution with electrophysiological recording is extremely good although specifying the neurochemical events that produce detected changes in neuronal activity is often indirect. The present experiments utilize an enzyme-based, glutamate-selective microelectrode array (MEA) that exhibits selectivity for extracellular glutamate and with a high degree of temporal and spatial resolution. Details of this amperometric detection of glutamate using the MEA have been summarized elsewhere [8].