Symposia

Symposia The new aspects of neurotransmitters and receptors in neuropsychiatric disorders／APSN/JSN合同シンポジウム

1S4-1 Stress and Relapse to Alcohol-Seeking Andrew J Lawrence Florey Institute of Neuroscience & Mental Health, University of Melbourne, Victoria, Australia Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Stress is a key precipitant of relapse, and relaxin-3 signalling modulates both stress responses and alcohol intake. We therefore examined a role for the relaxin-3 system in alcohol-seeking. In iP rats, icv microinjection of a selective RXFP3 antagonist prevented yohimbine-induced reinstatement of alcohol-seeking, discrete microinjections implicated the dorsal bed nucleus of the stria terminalis (BNST) as a locus. Using RXFP3-Cre x TdTomato reporter mice we set out to phenotype RXFP3-positive neurons in the BNST. Dual labelling studies suggest that ~60% of RXFP3-positive cells are inhibitory (GABA and/or calbindin-positive) while ~35% are excitatory (vGlut2-positive). In addition some RXFP3-positive cells are closely apposed by corticotropin releasing factor (CRF)-containing fibres. Retrograde tracing studies suggest that RXFP3-positive cells in the dorsal BNST do not directly innervate the ventral tegmental area (VTA) but do so indirectly. Electrophysiological recordings of RXFP3-positive cells in the dorsal BNST suggest at least 4 types of neurons based on firing properties, which are responsive to bath applied CRF and also show persistent adaptation after swim stress. Collectively, these data further implicate RXFP3 signalling within the dorsal BNST in relation to stress reactivity and relapse.		1S4-2 Balance of excitatory-inhibitory transmission in the developing vestibular nucleus tunes the brain circuitry for navigation Ying Sing Chan，Q.F. Jiang，S.K. Lai，K.L.K. Wu，C.W. Ma，D.K.Y. Shum School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Sassoon Road, Hong Kong, PR China Activity-dependent synaptic plasticity plays a key role in the refinement of neural circuits and expression of behaviors during development. It is unclear if synaptic plasticity of excitatory and inhibitory transmission in the developing circuit of the vestibular nucleus impacts on behavioral outcome. We demonstrated that the efficacy of glutamatergic synapses in the vestibular nucleus enabled postnatal emergence of graviceptive reflex in rats. Modulating the pre- and postsynaptic plasticity of GABAergic synapses also shifted the time for postnatal emergence of this behavior. Neonatal perturbation of glutamate or GABA receptor-mediated transmission not only deterred the establishment of internal spatial map in relay stations of the mature vestibular system but also caused lasting deficits in spatial cognition well into adulthood. Taken together, balance of excitatory and inhibitory synapses in the developing vestibular network is critical for orchestrating behavioral presentation of spatial recognition.[HKRGC-GRF 762313, 17131816; NSFC-RCG N_HKU735/14]

1S4-3 Targeting NMDA receptors for neuroprotection and anti-neuroinflammation Chian-Ming Low^1,2，C-Y Ng³，J Y-Y Tan¹，P T-H Wong¹，M-L Go⁴，T X-W Kwok³，F C-K Tan²，Y Lam³ ¹Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore，²Department of Anaesthesia, Yong Loo Lin School of Medicine, National University of Singapore，³Department of Chemistry, Faculty of Science, National University of Singapore，⁴Department of Pharmacy, Faculty of Science, National University of Singapore Over-activation of N-methyl-D-aspartate (NMDA) receptors has been implicated in pathological disorders such as stroke and Alzheimer disease (AD) and a number of classes of subunit-selective GluN2B-containing NMDA receptors have emerged. (A) We evaluated the neuroprotective efficacy of a benzimidazole-derivative (XK2) in experimental stroke. XK2 showed high blood brain barrier permeation and reduced infarct volume dose-dependently, yielding a significant protection of 35% at 3 mg.kg-1. (B) We showed activation of neurons via NMDA receptors led to p25 generation and initiates astrogliosis. Inhibition of cPLA2 led to reduced astrogliosis. Arachidonic acid derivatives equipped with either one or two fluorescent groups attached to the tip of the alkyl chains were synthesized and shown to function as inhibitor and substrates probes of cPLA2. We report that the inhibitor probe (7OHCou-AACF3) exhibits dual functions of inhibition and imaging while the substrate probe (Flu7OHCou) could be used for activity assay. It remains to be seen the plausible beneficial effects of XK2 and 7OHCou-AACF3 combination treatment in attenuating neuroinflammation in AD.		1S4-4 Lower expression of Regulator of G Protein Signaling 4 in schizophrenia: Contribution for altered cortical excitation-inhibition balance. Sohei Kimoto，Yasunari Yamaguchi，Toshifumi Kishimoto Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, Japan Alterations in excitation–inhibition balance are known to affect cognitive function. N-methyl-d-aspartate receptor (NMDAR) hypofunction in the dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathology of schizophrenia. However, the molecular basis of NMDAR hypofunction in schizophrenia remains poorly defined. NMDAR activity is negatively regulated by some G protein-coupled receptors (GPCRs). Signaling through these GPCRs is reduced by Regulator of G protein Signaling 4 (RGS4). Thus, lower levels of RGS4 would enhance GPCR-mediated reductions in NMDAR activity and could contribute to NMDAR hypofunction in schizophrenia. In this study, we quantified RGS4 mRNA and protein levels at several levels of resolution in the DLPFC from subjects with schizophrenia and matched healthy comparison subjects. To investigate molecular mechanisms that could contribute to altered RGS4 levels, we quantified levels of small noncoding RNAs, known as microRNAs (miRs), which regulate RGS4 mRNA integrity after transcription. RGS4 mRNA and protein levels were significantly lower in schizophrenia subjects and were positively correlated across all subjects. The RGS4 mRNA deficit was present in pyramidal neurons of DLPFC layers 3 and 5 of the schizophrenia subjects. In contrast, levels of miR16 were significantly higher in the DLPFC of schizophrenia subjects, and higher miR16 levels predicted lower RGS4 mRNA levels. These findings provide convergent evidence of lower RGS4 mRNA and protein levels in schizophrenia that may result from increased expression of miR16. Given the role of RGS4 in regulating GPCRs, and consequently the strength of NMDAR signaling, these findings could contribute to the molecular substrate for NMDAR hypofunction in DLPFC pyramidal cells in schizophrenia.