2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Schizophrenia

Pre-mRNAs of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propanoic acid (AMPA)/kainate glutamate receptors undergo post-transcriptional modification known as RNA editing that is mediated by adenosine deaminase acting on RNA type 2 (ADAR2). This modification alters the amino acid sequence and function of the receptor. Glutamatergic signaling has been suggested to have a role in mood disorders and schizophrenia, but it is unknown whether altered RNA editing of AMPA/kainate receptors has pathophysiological significance in these mental disorders. In this study, we found that ADAR2 expression tended to be decreased in the postmortem brains of patients with schizophrenia and bipolar disorder.. Decreased ADAR2 expression was significantly correlated with decreased editing of the R/G sites of AMPA receptors. In heterozygous Adar2 knockout mice (Adar2+/- mice), editing of the R/G sites of AMPA receptors was decreased. Adar2+/- mice showed a tendency of increased activity in the open-field test and a tendency of resistance to immobility in the forced swimming test. They also showed enhanced amphetamine-induced hyperactivity. There was no significant difference in amphetamine-induced hyperactivity between Adar2+/- and wild type mice after the treatment with an AMPA/kainate receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline.. These findings collectively suggest that altered RNA editing efficiency of AMPA receptors due to down-regulation of ADAR2 has a possible role in the pathophysiology of mental disorders.

Topics: Adenosine Deaminase; Animals; Behavior, Animal; Brain; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mood Disorders; Motor Activity; Postmortem Changes; Quinoxalines; Receptors, AMPA; Receptors, Glutamate; RNA Editing; RNA-Binding Proteins; Schizophrenia

Non-competitive antagonists of the N-methyl-d-aspartate receptor (NMDA) such as phencyclidine (PCP) elicit schizophrenia-like symptoms in healthy individuals. Similarly, PCP dosing in rats produces typical behavioral phenotypes that mimic human schizophrenia symptoms. Although schizophrenic behavioral phenotypes of the PCP model have been extensively studied, the underlying alterations of intrinsic neuronal properties and synaptic transmission in relevant limbic brain microcircuits remain elusive. Acute brain slice electrophysiology and immunostaining of inhibitory neurons were used to identify neuronal circuit alterations of the amygdala and hippocampus associated with changes in extinction of fear learning in rats following PCP treatment. Subchronic PCP application led to impaired long-term potentiation (LTP) and marked increases in the ratio of NMDA to 2-amino-3(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor-mediated currents at lateral amygdala (LA) principal neurons without alterations in parvalbumin (PV) as well as non-PV, glutamic acid decarboxylase 67 (GAD 67) immunopositive neurons. In addition, LTP was impaired at the Schaffer collateral to CA1 hippocampal pathway coincident with a reduction in colocalized PV and GAD67 immunopositive neurons in the CA3 hippocampal area. These effects occurred without changes in spontaneous events or intrinsic membrane properties of principal cells in the LA. The impairment of LTP at both amygdalar and hippocampal microcircuits, which play a key role in processing relevant survival information such as fear and extinction memory concurred with a disruption of extinction learning of fear conditioned responses. Our results show that subchronic PCP administration in rats impairs synaptic functioning in the amygdala and hippocampus as well as processing of fear-related memories.

Topics: Action Potentials; Amygdala; Animals; Area Under Curve; Biophysics; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Extinction, Psychological; Fear; Glutamate Decarboxylase; Hippocampus; In Vitro Techniques; Male; Memory Disorders; Neurons; Parvalbumins; Patch-Clamp Techniques; Phencyclidine; Quinoxalines; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Schizophrenia; Synaptic Transmission; Time Factors

The novel serotonin receptor subtypes, 5-HT6 and 5-HT7, are located in limbic regions and have nanomolar affinities for atypical antipsychotics. These factors have led some to speculate about the involvement of 5-HT6 and 5-HT7 receptors in schizophrenia. However, relatively little is known about these receptor subtypes, including the regulation of their expression in limbic regions. In particular, the regulation of extracellular serotonin levels in the striatum and hippocampal formation by glutamate receptors led us to examine the effects of systemic ionotropic glutamate receptor modulator treatment on 5-HT6 and 5-HT7 receptor expression in these regions. MK-801 treatment induced a dose-dependent decrease in striatal 5-HT6 receptor mRNA levels; similarly, both aniracetam and NBQX treatments also led to decreases in striatal 5-HT6 receptor mRNA levels. Hippocampal 5-HT6 and 5-HT7 receptor expression were not dramatically affected by any of the treatments. To our knowledge, this is the first demonstration of the regulation of striatal 5-HT6 receptor mRNA expression, and provides neurochemical anatomical evidence for the interaction of serotonergic and glutamatergic systems. Furthermore, although these two neurotransmitter systems are separately implicated in schizophrenia, the glutamatergic regulation of the expression of a receptor subtype associated with schizophrenia suggests that alterations in serotonin receptor expression in schizophrenia may result, in part, from altered glutamatergic activity.

Topics: Animals; Corpus Striatum; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Male; Nootropic Agents; Pyrrolidinones; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Receptors, Serotonin; RNA, Messenger; Schizophrenia