A schizophrenia-related sensorimotor deficit links α3-containing GABA _A receptors to a dopamine hyperfunction

Abstract

Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the ␣3 subunit of the GABAA receptor. ␣3 knockout (␣3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA A-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by ␣2-containing GABAA receptors, was preserved. As a result of the loss of ␣3 GABAA receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in ␣3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the ␣3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamineinduced hyperlocomotion was not altered in ␣3KO mice compared with WT mice. These results suggest that the absence of ␣3-subunit-containing GABAA receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at ␣3-containing GABAA receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions. haloperidol ͉ sensorimotor gating

Association of TMEM18 variants with BMI and waist circumference in children and correlation of mRNA expression in the PFC with body weight in rats

“…Knockout studies have shown this subunit to be involved in sensorimotor signaling and a hyperdopaminergic phenotype, which has been suggested to be related to schizophrenia. 39 The correlation of the expression of these genes in the PFC of rats with high body weight indicates PFC serotonergic and adrenergic signaling to be affected in these animals with concurrent effects on monoaminergic receptor expression and subsequent effects on GABA-receptor gene transcription.…”

Dysregulation of kisspeptin and neurogenesis at adolescence link inborn immune deficits to the late onset of abnormal sensorimotor gating in congenital psychological disorders

“…EAE was induced in adult offspring of control or poly-I:C-treated rats by immunization with MBP 68-86 emulsified in CFA, 29 and clinical symptoms of encephalomyelitis were monitored daily. The offspring of poly-I:C-treated rats showed a delayed onset and a shorter duration of EAE symptoms following MBP [68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86] vaccination, compared to the controls (Table 1b). These results supported our contention that immune activation during pregnancy is associated with reduced immune response to brain antigens in the offspring.…”

“…As expected, adult offspring of the poly-I:Ctreated rats showed a reduction in PPI compared to the progeny of saline-treated animals (Supplementary Figure 1). To measure alterations in immunity to brain-specific antigens in the poly-I:C-affected offspring, we vaccinated female and male offspring at adulthood with the myelin basic protein (MBP)-derived peptide, MBP 68-86 , a CNS-associated self-antigen known to be the immune-dominant epitope in this strain, 33 and examined lymphocyte proliferation in response to the injected antigen, MBP [68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86] , as well as to Con-A, a lymphocyte mitogen, or to Ova (an irrelevant antigen). We found, in lymphocytes of the offspring of the poly-I:C-treated animals, a significant reduction in the proliferative response to MBP (Table 1a).…”

“…Adult rats were immunized at the base of the tail with 75 mg of the peptide MBP [68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86] (YGSLPQKSQR-SQDENPV) 27 (synthesized at the Weizmann Institute of Science), emulsified in an equal volume of complete Freund's adjuvant (CFA; DIFCO LABORA-TORIES, Detroit, MI, USA) containing 5 mg ml…”

Patients with Premenstrual Dysphoric Disorder have Increased Startle Response Across both Cycle Phases and Lower Levels of Prepulse Inhibition During the Late Luteal Phase of the Menstrual Cycle

“…The sensorimotor gating of the ASR is also subject to regulation by the putative causative agents of PMDD, including steroid hormones and dysregulation of inhibitory neurotransmission. Sensorimotor gating is regulated by GABA A receptors in several relevant brain regions, notably the amygdala and the bed nucleus of the stria terminalis (BNST) Yee et al, 2005;Hauser et al, 2005). Ovarian steroids also appear to influence PPI because women have lower levels of PPI than men (Swerdlow et al, 1993) and because PPI varies across the menstrual cycle in healthy women (Jovanovic et al, 2004;Swerdlow et al, 1997).…”