神経調節物質とシナプス Neuromodulators and synaptic plasticity
O2-6-2-1 コルチコステロンは抗うつ薬誘導性の海馬神経可塑性を促進する Corticosterone facilitates antidepressant-induced neuronal plasticity in the hippocampus ○小林克典1,2, 池田裕美子1, 浅田穣1, 稲垣弘文3, 川田智之3, 鈴木秀典1,2 ○Katsunori Kobayashi1,2, Yumiko Ikeda1, Minoru Asada1, Hirofumi Inagaki3, Tomoyuki Kawada3, Hidenori Suzuki1,2 日本医大・薬理1, 日本医大・衛生・公衆衛生3 Dept Pharmacol, Grad Sch Med, Nippon Med Sch, Tokyo1, JST, CREST2, Dept Hyg Publ Hlth, Grad Sch Med, Nippon Med Sch, Tokyo3 The hippocampal dentate gyrus has been implicated in a cellular mechanism of antidepressant action. We have recently demonstrated a distinct form of neuronal plasticity induced by the serotonergic antidepressant fluoxetine in mice, that is, a reversal of maturation of the granule cells in the adult dentate gyrus. This dematuration is induced in a large population of dentate neurons and maintained for at least one month after withdrawal of fluoxetine, suggesting long-lasting strong influence of dematuration on brain functioning. However, reliable induction of dematuration required doses of fluoxetine higher than suggested optimal doses for mice (10 to 18 mg/kg/day). Since our previous studies were performed using naive mice, in the present study, we reexamined effects of fluoxetine using mice treated with chronic corticosterone that model neuroendocrine disturbance associated with mood disorders. In corticosterone-treated mice, fluoxetine at 10 mg/kg/day reduced expression levels of mature granule cell markers and attenuated strong frequency facilitation at the synapse formed by the granule cell axon mossy fiber, suggesting the induction of granule cell dematuration. In addition, fluoxetine strongly enhanced dopaminergic modulation at the mossy fiber synapse. In vehicle-treated mice, however, fluoxetine at this dose had no significant effects. The plasma level of fluoxetine was comparable to those in patients taking chronic fluoxetine, and corticosterone did not affect it. These results indicate that corticosterone facilitates fluoxetine-induced neuronal plasticity in the dentate gyrus and at the mossy fiber synapse. Our present finding may provide insight into the neuronal basis for enhanced responsiveness to antidepressant medication in certain pathological conditions.	O2-6-2-2 培養神経回路網におけるノルアドレナリン修飾作用の情報量解析 Information content analysis of noradrenergic modulation in neuronal networks ○門倉智之助1, 磯村拓哉1, 有松和之1, 小谷潔1, 神保泰彦1 ○Tomonosuke Kadokura1, Takuya Isomura1, Kazuyuki Arimatsu1, Kiyoshi Kotani1, Yasuhiko Jinbo1 東京大院 新領域 人間環境学1 Dept Human Envir, Univ of Tokyo, Chiba, Japan1 The role of neuromodulators on memory and synaptic plasticity attracts a great deal of attention. Especially, noradrenaline (NA) is thought to contribute to memory consolidation. Although researchers have discussed noradrenergic modulation in a neuron, less is known at the neuronal network level because of the difficulties in recording and analysis of multi-neuronal activity. We investigated noradrenergic modulation in cultured neuronal networks by calculating information content. We cultured dissociated rat cortical neurons on microelectrode array dish. We recorded spontaneous activity both before and after 1 μM NA application. To evaluate the effect of NA on synaptic plasticity, we applied tetanic stimulation to two electrodes in the presence of 1 μM NA and recorded spontaneous activity and electrically evoked response to test stimulus. Connection strengths between neurons was estimated by calculating delayed transfer entropy (DTE) from obtained spontaneous spike data and counting the number of post-neuronal spikes evoked by test stimulus applied to pre-neuron. We observed that 1 μM NA application induced the increase of spontaneous firing rate and DTE in the neuronal networks. In the presence of NA, tetanic stimulation induced significant change of DTE between neurons which were directly stimulated. Mutual evoked response of neuronal groups at two stimulated electrode decrease after pairwise tetanic stimulation. On the other hand, in the absence of NA, tetanic stimulation induced almost no change of DTE and evoked response. These results indicate that NA increases excitability and transmission efficiency of cultured neuronal networks. Facilitation of synaptic plasticity induced by NA suggests that NA shifts neuronal networks into soft state in which neurons can easily change their transmission efficiency.
O2-6-2-3 Endocannabinoid-Mediated Modulation of Inhibitory Synaptic Transmission to GABAergic and non-GABAergic Neurons in the Bed Nucleus of the Stria Terminalis (BNST) ○Ako Kato1, Yuchio Yanagawa2, Masanobu Kano1 Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan1, Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan2 The BNST, a part of the extended amygdala that is included in the limbic system, is densely innervated by GABAergic neurons. Changes in the BNST have been described to play an important role not only in the behavioral responses such as stress, anxiety and fear but also in the affective component of pain. It is known that CB1 receptors are expressed in the BNST and that endogenous cannabinoids (endocannabinoids) modulate synaptic plasticity. Although several studies in rodents have already shown that cannabinoids are able to diminish sensory pain responses in several pain models, their contribution to affective pain remains still unknown. Here we aim to clarify how the endocannabinoid signaling controls inhibitory synaptic transmission onto GABAergic and non-GABAergic neurons within BNST and whether the endocannabinoid system contributes to affective component of pain. Whole-cell patch clamp recordings of inhibitory postsynaptic currents (IPSCs) were performed in acutely isolated transverse brain slices of GAD67GFP mice, which allowed targeted recordings from non-GABAergic (GAD67GFP-negative) and GABAergic (GAD67GFP-positive) neurons. Perfusion of low concentration of DHPG (10μM), an mGluR 1/5 receptor agonist, transiently diminished IPSC amplitudes in non-GABAergic neurons by 26.02±3.40% (n=7). This inhibition was reversed by the CB1R antagonist AM251 (5μM) suggesting that it is a CB1 receptor-mediated effect. However, no effect of DHPG was observed in GABAergic neurons (-4.22±6.38%, n=6). In contrast, depolarization-induced suppression of inhibition (DSI) could be elicited in both non-GABAergic (5 out of 6) and GABAergic (4 out of 7) neurons. These results suggest that inhibitory input to non-GABAergic, but not to GABAergic, neurons is sensitive to endocannabinoids released by low concentration of DHPG. This phenomenon may render non-GABAergic neurons more susceptible to activation by specific input from nociceptive (pain specific) and non-nociceptive fibers.	O2-6-2-4 視床中継細胞の phasic GABA 電流は末梢神経損傷により減弱するのに対し tonic GABA 電流は増加する Phasic-GABA current in thalamic relay neurons is reduced by peripheral nerve injury, whereas tonic-GABA current is increased ○南雲康行1, 宮田麻理子1,2 ○Yasuyuki Nagumo1, Mariko Miyata1,2 東京女子医科大学　医学部　第一生理1, さきがけ・科学技術振興機構2 Dept Physiol, Tokyo Women's Medical Univ, Tokyo1, PRESTO, Japan Science and Technology Agency, Saitama2 SOMATOSENSORY THALAMUS, GABAERGIC SYNAPTIC Several anatomical studies proposed that the decrease in GABA transmission in the thalamus is induced by the peripheral nerve injury. We have previously reported that the infraorbital nerve cut (IONC) operation resulted in multiple innervation of medial lemniscal fibers, which are excitatory synapses, onto thalamic ventral posterior medial (VPM) neurons around 5 days after operation (POD5). However, the detail of the postoperative change in inhibitory phasic and tonic GABA currents onto VPM neurons after the IONC operation remains still unclear. Here we report that the IONC operation reduced the amplitude of evoked-inhibitory postsynaptic currents (eIPSCs) by minimum stimulation of TRN in mouse VPM neurons from POD1 to POD7. Similarly, the amplitude of miniature IPSCs (mIPSCs) by asynchronous release and spontaneous IPSCs (sIPSCs) were also reduced by the IONC operation. In contrast, tonic GABA currents onto VPM neurons significantly increased by the IONC operation at POD1. These changes were still observed in multiple VPM neurons, which had multiple lemniscal fibers by the IONC operation, at POD7. Interestingly, these changes were not observed in non-multiple VPM neurons, which have single multiple lemniscal fibers in IONC mice at POD7. Moreover, the ratio of inhibitory/excitatory total charge of VPM neurons was significantly increased in IONC mice at POD1 and POD7. Our results indicate that the contrary change in GABAA-receptor mediated phasic- and tonic-currents occurred earlier than the recruitment of additional lemniscal fibers onto VPM neurons after the IONC operation. These GABAergic changes may link to the medial lemniscal fiber's rewiring induced by the IONC operation.

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