Symposia

Symposia Roles of dopaminergic neurotransmission in mental disorders／精神疾患におけるドーパミン神経伝達の役割

3S8-1 Roles of developing processes of dopaminergic neurons in neuropsychiatric disorders Shuken Boku Dept Psychiatry. Grad Sch Med Kobe Univ It is well known that dopaminergic neurons play a pivotal role in neuropsychiatric disorders such as schizophrenia, bipolar disorder, major depression, addictions and attention deficit hyperactivity disorder (ADHD). Especially, it is also well known that developing processes of brains have powerful effects on the pathophysiology of schizophrenia and ADHD. There are two major pathways of dopaminergic neurons: mesocorticolimbic pathway and nitrostriatal pathway. In these pathways, mesocorticolimbic pathway, consisting of A10 dopaminergic neurons, is involved in neuropsychiatric disorders. These suggest that developing processes of A10 dopaminergic neurons may be strongly involved in the pathophysiology of schizophrenia and ADHD. In addition, it is shown that the characters of A10 dopaminergic neurons are different from those of A9 dopaminergic neurons. Taken together, these suggest that developing processes of A10 dopaminergic neurons may play a role in the pathophysiology of schizophrenia and ADHD. Therefore, elucidating detailed molecular mechanisms of developing processes of A10 dopaminergic neurons is expected to lead to further understanding of the pathophysiology of schizophrenia and ADHD and the development of new therapy of these disorders. However, it even remains unclear how A10 dopaminergic neurons are differentiated from neural stem cells. Here, we first review the past studies of roles of developing processes of brains in schizophrenia and ADHD and molecular mechanisms of the differentiation of dopaminergic neurons from neural stem cell. Then, we discuss the potential molecular mechanisms of the differentiation of A10 dopaminergic neurons from neural stem cells and the application of it to the development of new therapy of schizophrenia and ADHD.		3S8-2 Analysis of dopamine transporter knockout mice as an animal model of psychiatric disorders Yoshiyuki Kasahara^1,2，Yumiko Kubo¹，Yosefu Arime^1,3，Ichiro Sora^1,4 ¹Dept Biol Psychiatry, Grad Sch Med, Tohoku Univ，²Adv Interdisciplinary Biomed Engineering, Grad Sch Med, Tohoku Univ，³Dept Biol Psychiatry Neurosci, Sch Med, Dokkyo Med Univ，⁴Dept Psychiatry, Grad Sch Med, Kobe Univ Dopamine transporter (DAT) is integral membrane protein that removes dopamine from the synaptic cleft and deposits it into surrounding cells, thus terminating the signal of the neurotransmitter. DAT knockout (KO) mice show numerous behavioral alterations including hyperlocomotion, impulsivity, cognitive deficits, and impairment of prepulse inhibition of the startle reflex (PPI), phenotypes that may be relevant to frontostrial disorders such as schizophrenia and attention deficit / hyperactivity disorder (AD/HD). DAT KO mice exhibit persistently and profoundly elevated extracellular dopamine levels in the striatum and nucleus accumbens. Nisoxetine, a selective norepinephrine transporter (NET) inhibitor, reversed the PPI deficit in DAT KO mice, and region specific infusion of nisoxetine into the medial prefrontal cortex (mPFc) also reversed PPI in DAT KO mice. Moreover, both hyperactivity and impulsivity observed in DAT KO mice were ameliorated by treatment with methylphenidate and nisoxetine. Impairment of neuronal development in the PFc are observed in a number of psychiatric disorders such as schizophrenia and AD/HD. We found a significant decrease in spine density of pyramidal neurons in the mPFc in DAT KO mice compared with wild type mice. Spine density of the CA1 regions of the hippocampus in DAT KO mice were also decreased. We speculate that decreased spine density could cause hypofunction of the mPFc, and contribute to the behavioral abnormalities observed in DAT KO mice.

3S8-3 Transcriptome profiling of dopamine-deficient mouse brain Shinya Kasai¹，Yoko Hagino¹，Masayo Fujita¹，Kazuto Kobayashi²，Kazutaka Ikeda¹ ¹Addict Substance Proj, Tokyo Metro Inst Med Sci，²Dept Mol Genet, Inst Biomed Sci, Fukushima Med Univ Dopamine neurons project to some distinct areas via mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways. Dopaminergic neurons are also regulated from other neurotransmitters’ systems including other monoaminergic, cholinergic, glutaminergic, and GABAergic neurons. Therefore, dopamine imbalance is hypothesized to alter these neurotransmissions but also gene expressions related to dopamine and other neurotransmitters. In this study, we analyzed transcriptome profiling in dopamine-deficient mice for elucidating the influence of dopamine levels on the other neurotransmitters' systems.Dopamine-deficient mice were generated by tyrosine hydroxylase (Th) gene knockout with Th transgene under a dopamine β-hydroxylase gene promoter. Gene expression profiles in the brains of dopamine-deficient mice were analyzed with Illumina MouseRef-8 Expression BeadChips.The gene expression of the aromatic L-amino acid decarboxylase was increased, but gene expression of catechol-O-methyltransferase and monoamine oxidase A/B were not altered in dopamine-deficient mice. In contrast, choline acetyltransferase gene expression was decreased and acetylcholinesterase gene expression was unaltered in the basal ganglia of dopamine-deficient mice. The gene expressions of histidine decarboxylase and diamine oxidase of the histamine biosynthesis pathway were increased and decreased, respectively, in the brainstem of dopamine-deficient mice. These data suggest that serotonergic and histaminergic neurotransmissions may be activated while on the contrary cholinergic neurons may be inactivated in dopamine-deficient mice. In the symposium, we also discuss whole-genome gene expression changes and related pathways in dopamine-deficient mice.		3S8-4 Discovery of a novel intracellular dopamine D2 receptor function Kohji Fukunaga¹，Norifumi Shioda²， ¹ ¹Dept Pharmacol, Grad Sch Pharm Sci, Tohoku Univ，²Dept Mol Biol, Gifu Pharm Univ Dopamine dysfunction is believed to be one of the causes of disorders like Schizophrenia, Tourette's syndrome, Attention Deficit Hyperactivity Disorder and Parkinson's disease. To elucidate novel therapeutics for the intractable psychotic diseases, we define the novel function of intracellular dopamine receptor (D2LR)(1). We identified novel D2LR binging protein Rabex-5 and investigated it functions in dopamine neurons. Dendritic spine density in striatopallidal MSNs after quinpirole treatment was measured in wilt-type mice and D2LR knockout mice. D2LR is localized to intracellular compartment such as early endosome in neurons. The intracellular D2LR elicits extracellular signal-regulated kinase (ERK) activation and dendritic spine formation through Rabex-5/platelet-derived growth factor receptor-β (PDGFRβ)-mediated endocytosis in mouse striatum. D2LR directly binds to and activates Rabex-5, promoting early endosome formation. Endosomes containing D2LR and PDGFRβ are then transported to early endosome/Golgi apparatus, where those complexes trigger Gαi3-mediated ERK signaling. Loss of intracellular D2LR-mediated ERK activation decreased neuronal activity and dendritic spine density in striatopallidal medium spiny neurons (MSNs). Those spine changes were lacking D2LR knockout mice. Moreover, intracellular D2LR signaling mediated effects of a typical antipsychotic drug, haloperidol, in inducing catalepsy behavior. The novel intracellular D2LR signaling through Rabex-5/PDGFRβ is critical for prolonged ERK activation, thereby promoting dendritic spine formation and neuronal activity in striatopallidal MSNs of mice. This work was supported by KAKENHI 25293124 and 24102505 (KF). (1) Mol Psychiatry doi:10.1038/mp.2016.200.