Symposium

Symposium 14 Elucidation of signal transduction pathways in cognitive and mental disorders as targets for drug discovery シンポジウム14 創薬を目指した認知・精神疾患のシグナル病態の解明

SY14-1 Regulatory mechanisms of basal ganglia in cognitive learning and mental disorders 大脳基底核における認知学習と精神疾患の制御機構 Hikida Takatoshi（疋田貴俊） Institute for Protein Research, Osaka University The basal ganglia play a critical role in motor functions as well as cognitive functions and dysfunctions. In the basal ganglia network, the inputs of the striatum/nucleus accumbens are transmitted through two parallel direct and indirect pathways and controlled by dopamine transmitter. We have developed transgenic mouse models to dissect neural circuit mechanisms in cognitive learning and pathophysiology of mental disorders. Using reversible neurotransmission blocking (RNB), we developed D-RNB and I-RNB mouse models in which transmission-blocking tetanus toxin is expressed in the direct striatonigral or the indirect striatopallidal pathway and, in turn, blocked each pathway in a doxycycline-dependent manner. We have revealed the distinct role of the two striatal pathways in cognitive functions and dysfunctions: the direct pathway critical for reward-based learning and development of cocaine addiction, and the indirect pathway for aversive learning and learning flexibility. We propose a new circuit mechanism that the dopaminergic input from ventral tegmental area can switch the direct and indirect pathway in the nucleus accumbens. These basal ganglia circuit mechanisms will give us insights into the pathophysiology of mental disorders.		SY14-2 High content imaging to drug repositioning for neuropsychiatric disorders ハイコンテントイメージングを用いたシナプス病態解析技術とドラッグデポジショニングへの挑戦 Hayashi-Takagi Akiko（林（高木）朗子） Lab of Medical Neurosci, Gunma Univ, Gunma, Japan The deterioration of the synapses has attracted attention as the pathophysiology of neuropsychiatric disorders, and synaptic responses against the stress, such as oxidative, endoplasmic reticulum, and carbonyl stress, is considered as a possible causal signaling in these diseases. Thus, we have developed the high content in vitro screening system as well as in vivo 2-photon synaptic imaging of disease models. With use of the validated compound library that consists of 1280 compounds with known bioactivity (Drug Discovery Initiative, University of Tokyo), we have screened compounds with the protective effect on the phencyclidine-induced synaptic deterioration and carbonyl stress by measuring the quantitative measurement of the synapse and stress-related metabolites. Together with behavioral assessment, we are now challenging to find a compound that can be applied for the drug repositioning for neuropsychiatric disorders.

SY14-3 Exploring molecular pathways involved in central amygdala-dependent control of emotional behaviors 扁桃体中心核を介した情動行動制御の分子機構探索 Takemoto-Kimura Sayaka（竹本さやか）^1,2，上田修平¹，尾藤晴彦³ ¹Res. Inst. Environ. Med., Nagoya Univ., Nagoya, Japan ²PRESTO-JST, Saitama, Japan ³Dept. of Neurochemistry, Grad. Sch. of Medicine, The Univ. of Tokyo, Tokyo, Japan Social and emotional behavior disabilities are exhibited in multiple psychiatric disorders. In addition to its well-known role as mediating fear and anxiety responses, the amygdala is a region in the brain that is crucial for social processing. Within the amygdala, the basolateral amygdala (BLA)-central nucleus of amygdala (CeA) circuit is known to mediate fear and anxiety responses. However, the involvement of this circuit in social behavior and its molecular basis remain to be elucidated. We found that the BLA is activated during social encounters, which indicates that this circuit is involved in social behavior regulation. To investigate the molecular basis of CeA-dependent social and emotional behaviors, we focused on a Ca²⁺-dependent phosphorylation pathway, which is highly expressed in the CeA. We hypothesized that the Ca²⁺-signaling is essential in the activity-dependent establishment of information processing in the amygdala, specifically impacting the amygdala-dependent emotional and social behaviors within the local circuit in the CeA. In accordance with this hypothesis, genetic and virus-mediated molecular manipulations of the kinase induced behavioral anomalies in emotional and social behavioral tasks. Furthermore, histological studies revealed the enrichment of the kinase in a subset of inhibitory neurons located in the CeA. Taken together, our study identify a novel amygdala Ca²⁺-dependent signaling pathway that controls behavioral modifications triggered in response to external social environment.		SY14-4 Development of novel Alzheimer's disease therapeutics as targets for K_ATP channel K_ATPチャネルを標的とした新規アルツハイマー病治療薬の開発 Moriguchi Shigeki（森口茂樹），福永浩司 Dept. Pharmacol. Grad. Sch. Pharmaceut. Sci. Tohoku Univ. Memantine ameliorates progressive symptomes in Alzheimer’s disease (AD) through moderate inhibition of N-methyl-D-aspartate receptors (NMDARs). Here we report that a novel target of mementine, ATP-sensitive K+ (KATP) channels are implicated in memory improvement. KATP channels Kir6.1 or Kir6.2 are composed with sulfonylurea receptors (SURs), which are distributed both in peripheral tissues and central nervous system. We confirmed that memantine improves both memory impairment and perturbed NMDAR-dependent LTP in APP23 mouse hippocampus. Unexpectedly, memantine in vivo increased CaMKII activity in APP23 hippocampus, and memantine-induced enhancement of hippocampal LTP and CaMKII activity was in vitro abolished by treatment with pinacidil, a specific opener of KATP channels. We therefore confirmed that memantine inhibits KATP channels Kir6.1 and Kir6.2 and elevates intracellular Ca2+ concentrations by inhibition of Kir6.1 or Kir6.2. Kir6.2 was preferentially expressed in the postsynaptic regions, whereas Kir6.1 was predominant in mouse hippocampal neuron dendrites. Finally, we confirmed that Kir6.2 heterozygous mutant mice exhibit severe memory deficits and hippocampal LTP impairment that could not be rescued by memantine administration. Taken together, we propose a novel strategy that memantine inhibits Kirs 6.2/6.1 activities, thereby improving memory impairment in AD patients.