Symposium
Breakthrough that links basic neuroscience and potential therapeutic strategies for neuropsychiatric disorders
シンポジウム
地道な基礎神経科学から創薬へのブレークスルー |
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| 7月28日（日）8:45～9:15 第2会場（朱鷺メッセ 2F メインホールA）
4S02m-1
アルツハイマー病周辺症状を標的とした新規メカニズムの探索
Shigeki Moriguchi（森口 茂樹），Kohji Fukunaga（福永 浩司）
東北大学大学院薬学研究科薬理学分野
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. | | 7月28日（日） 9:15～9:45 第2会場（朱鷺メッセ 2F メインホールA）
4S02m-2
シナプス可塑性：基礎から臨床へ
Takuya Takahashi（高橋 琢哉）
横浜市立大学大学院医学研究科生理学
Glutamatergic synapses play central roles in almost all of neuronal functions such as learning, motor and sensory functions. Among glutamate receptors, AMPARs are the "" actual mediator"" at glutamatergic synapses. Since the cloning of AMPARs approximately two decades ago, enormous number of papers have reported the importance of AMPARs on neuronal functions including diseases. Despite the accumulation of knowledge of physiological roles of AMPARs, its clinical translation is limited. Main reason for this is that we are not able to visualize AMPARs in living human brain. Although rodent neuronal disease models are elegant and well characterized, it remains unclear if these animal models fully mimic human disease. Characterization of these diseases with AMPARs in living human brain should provide us biological basis of neuropsychiatric disorders.
We developed novel PET probe for AMPARs. We detected specific PET signals of AMPAR in rat, non-human primate and human. We could visualize the accumulation of PET signals of AMPAR in the temporal lobe of the hemisphere with epileptic foci where the 99mECD-SPECT blood flow signal was lower compared to the contralateral hemisphere. Further, we detected significant positive correlation between AMPAR-PET-signals and protein amount of AMPARs with surgically removed tissue from epileptic patients. Thus, our PET probe for AMPARs specifically detects AMPARs and the first PET probe to visualize AMPAR in living human brain. We are currently imaging patients with neuropsychiatric disorders.
Further, we have recently identified CRMP2-binding compound, edonerpic maleate, facilitates synaptic AMPAR delivery and results in the acceleration of motor function recovery after brain damage in rodent and non-human primate.These small compounds will be promising tools to translate the knowledge of synaptic physiology to the elucidation of human neuropsychiatric disorders and brand-new clinical settings. | | 7月28日（日） 9:45～10:15 第2会場（朱鷺メッセ 2F メインホールA）
4S02m-3
人工的シナプス制御ツールの開発とその応用に向けて
Michisuke Yuzaki（柚崎 通介）
慶應大医生理
Synapses are not only formed during development, but also undergo functional and structural changes in an activity-dependent manner throughout life. Imbalance in excitatory and inhibitory synapses is thought to underlie various neurodevelopmental, neuropsychiatric and neurological disorders. Nevertheless, whether and how synaptic abnormalities in particular neuronal circuits lead to certain behavioural phenotypes remain largely unclear mainly due to the lack of tools that could acutely modify synaptic connections in vivo. Synaptic organizing proteins are classified into three major categories: cell adhesion molecules, such as neurexins (Nrxs) and neuroligins, diffusible factors, such as fibroblast growth factors and Wnt, and secreted extracellular scaffolding proteins (ESPs), such as Cbln1 and neuronal pentraxin 1 (NP1). Cbln1, a prototype of ESPs, forms a transsynaptic complex at cerebellar granule cell-Purkinje cell synapses by simultaneously binding to presynaptic Nrxs and postsynaptic delta2 glutamate receptors (GluD2). A single injection of recombinant Cbln1 into the cerebellum can rapidly and potently induce synapses and restore normal motor coordination in adult Cbln1-null mice in vivo. However, to modify synaptic connectivity in various neuronal circuits, a toolkit of ESPs with a variety of pre- and postsynaptic specificities is desired. In this talk, I would like to introduce our recently developed artificial ESP, Cbln1-NP1 chimera (CPTX). We found that CPTX induced excitatory synapses by co-recruiting postsynaptic AMPA glutamate receptors and presynaptic Nrxs in the hippocampus, as well as the cerebellum, in a manner independent of GluD2. Moreover, a single injection of CPTX regulated synaptic plasticity and learning in vivo. | | 7月28日（日）10:15～10:45 第2会場（朱鷺メッセ 2F メインホールA）
4S02m-4
シナプスパソロジーに着目した精神疾患研究および新規創薬標的の探索
Akiko Hayashi-Takagi（林 朗子）
理研・脳神経科学研究センター・多階層精神疾患研究チーム
Pharmacological treatment for psychiatric disorders started with chlorpromazine, whose efficacy as an antipsychotic was serendipitously discovered. Because the pathophysiology of psychiatric disorders remains largely unknown, drug discovery has been limited to chemical modifications of chlorpromazine, all of which have focused on blocking the dopamine and serotonin transmission. It is now widely accepted that drugs that specifically target a single molecule are likely to be less effective or to cause adverse side effects, which highlights the disappointing limitations of drug discovery by a single molecule target.
Based on epidemiology and human genetics, psychiatric disorders such as schizophrenia and depression are heterogeneous and polygenic disorders with shared characteristics at the cell and circuit level. In other words, psychiatric disorders are systemic diseases because malfunctions of systemic control result in the symptoms of these disorders. This, therefore, warrants a systems-oriented approach to more effectively control the robustness of living systems. These include cell-based phenotypic biology assays, in which in vitro neuron culture models can provide substantive information on various cellular responses following exposure to a library of small molecular compounds. To mimic the excitotoxicity, which is supposed to trigger the onset of schizophrenia, we use the NMDA receptor antagonist phencyclidine (PCP) to create animal models of schizophrenia in vitro. In our primary cortical neuron cultures, PCP has consistently been found to induce a drastic decrease in spine density and the accumulation of the schizophrenia-related metabolite, pentosidine. We are currently using a validated compound library, which consists of 1280 off-patent drugs, to screen for a neuroprotective compound that ameliorates spine deterioration and the accumulation of disease-related metabolites. For this, we have established a semi-automated and quantitative cell-based phenotypic assay. In this symposium, we will introduce hit compounds in our system, and its challenge for the drug repositioning as a novel therapeutic application for psychiatric disorders. | |
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