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Fruit flies-in vivo screening models for Alzheimer's and other CNS diseases

Fruit flies-in vivo screening models for Alzheimer's and oth...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Weiwei MA~1,I-Feng PENG~1,Yi ZHONG~(1,2,3,*) 1 Suzhou JoeKai Biotech LLC,Suzhou 215300,China 2 School of Life Science,Tsinghua University,Beijing 100084,China 3 Cold Spring Harbor Laboratories,Long Island,NY,11724,USA

In current drug discovery pipeline,in vitro biochemical and cell-based screening assays have been widely used before the validation tests in in vivo animal ***,the gap between two platforms sometimes impairs the discovery progress,especially for the diseases with complicated *** order to minimize such gap in the CNS disease area,we have developed several Drosophila models as supplementary approaches in parallel to the in vitro *** CNS fly models preserve behavioral deficits and pathological hallmarks similar to those observed in human patients,yet are low in running cost and are suitable for high-throughput screening *** fly Alzheimer's disease(AD) model was generated through targeted pan-neuronal expression of a transgene encoding a secretive form of human Aβ42 peptides in the Drosophila *** expression leads to neurodegeneration with accumulation of Aβ42 and fibril deposits in the brain area,which may lead to shortened life *** addition,AD flies also display severe age-dependent memory loss,highly mimicking dementia syndrome in AD ***-controlled massive screening devices were utilize in the fly memory(T-maze) system,enabling screening of hundreds of compounds per day in scale for industrial *** model for NFl,Noonan syndrome were developed for drug screening service,along with other CNS disease models such as Parkinson's disease(PD),schizophrenia,and autism that have also been planned for the pipelines in CNS drug discovery.

关键词： Alzheimer Fruit flies-in vivo screening models for Alzheimer's and other CNS diseases CNS

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Morphology change of secondary neuron under fast and slow photoreceptor degeneration

Morphology change of secondary neuron under fast and slow ph...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Qiang ZENG~1,Hai-Tao ZHANG~2,Yan YIN~1,Zhi-Ping LIU~1,Yi WANG~2,Zheng-Qin YIN~(2,*),Shi-Gang HE~(1,*) 1 State Key Laboratory of Brain and Cognitive Sciences,Institute of Biophysics,Chinese Academy of Sciences,15 Da- tun Road,Beijing 100101,China 2 Southwest Eye Hospital,Chongqing 400038,China

Objective To investigate the influence of photoreceptor degeneration on the morphology of secondary neurons(bipolar and horizontal cells) in the retina of Royal College of Surgeons(RCS) rat and light damaged(LD) albino *** RCS rats and LD mice retinas were sampled at different degeneration stages and compared with wild type(wt) retinas;Both immunohistochemistry and Dil labeling methods were used to examine lamination and morphology of the secondary *** were acquired by confocal microscopy and analyzed with ImageJ. Results Gradual loss of photoreceptors and ribbon synapses was detected from postnatal day 30(P30) to P90 in the RCS rat *** bipolar cells and horizontal cells kept the neurite lamination in outer plexiform layer(OPL) at P60 when 20%photoreceptors left;horizontal cells maintained their morphology at P45 when 50%photoreceptors *** induced fast loss of photoreceptors and ribbon synapses in albino mouse *** and morphology disruption of the bipolar cells happened at 1 day after light damage(DALD).Morphology change of horizontal cells appeared at 5 *** Structure alternation of secondary neurons in RCS rat retina appears later than photoreceptor loss during the slow degeneration *** in LD mouse retina the alternation appears early following fast photoreceptor loss,indicating the morphology change could happen fast and the residual photoreceptors maintain the structure of secondary neurons.

关键词： retina Royal College of Surgeons light damage horizontal cell bipolar cell

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Neural mechanisms of horizontal saccades in brain stem

Neural mechanisms of horizontal saccades in brain stem

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Yosikatu SHINODA Youriko SUGIUTHI Mayou TAKAHASHI Department of Systems Neurophysiology Graduate School of MedicineTokyo Medical and Dental UniversityTokyo 113-8519Japan

＜正＞Objective Saccades are rapid eye movements that orient gaze toward areas of interest in the visual scene, that playing an important role in capturing visual information quickly and accurately from the outside *** far as the known electrophysiological studies concerned:the horizontal saccades is close related to the physiological activities of excitatory burst neurons（EBNs）and inhibitory burst neurons（IBNs）in reticular formation of brainstem and the morphology of the ***,the detailed distribution and projection model of EBNs and IBNs in the brainstem hasn’t been clear *** purpose of this study is trying to find out the detailed distribution and projection model of EBNs and IBNs in the brainstem associated with rapid eye movement,to further explore the neural control mechanisms of the occurrence of rapid eye *** Using electrophysiology, nerve tissue anatomy,neuronal markers and re-building as research *** EBNs were located in the dorsomedial reticular formation of pons,in addition to projecting to the ipsilateral Abd,there were branches separately projecting to the ipsilateral IBNs,nucleus prepositus hypoglossi（PH）and medial vestibular nucleus （MVN）;IBNs were located in the dorsomedial end of ipsilateral Abd,in addition to projecting to the opposite Abd,there were branches projecting to the contralateral IBNs and *** in the rostral superior colliculus were related to fixation of visual attention,and neurons in the caudal superior colliculus were related to rapid eye *** in the rostral superior colliculus were projecting to the midline omnipause neurons（OPNs）in the contralateral reticular formation of brain stem,and neurons in the caudal superior colliculus were projecting to the contralateral EBN and IBN in the reticular formation of *** were projecting to the contralateral EBNs and *** results of this study revealed the control mechanism of horizontal eye movement and the importance

关键词： horizontal rapid eye movement excitatory burst neurons（EBNs） inhibitory burst neurons（IBNs）

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Region-specific involvement of BDNF secretion and synthesis in conditioned taste aversion memory formation

Region-specific involvement of BDNF secretion and synthesis ...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Francis S.Lee Department of Psychiatry Weill Cornell Medical College of Cornell UniversityNew YorkNew York 10065USA

＜正＞Objective Brain-derived neurotrophic factor（BDNF） and its receptor,tropomyosin-related kinase receptor B（TrkB）,play a critical role in activity-dependent plasticity processes such as long-term potentiation,learning, and *** has been shown that BDNF exerts different or even opposite effects on behavior depending on the neural ***,the detailed role of BDNF in memory process on the basis of its location has not been fully ***,we aim to investigate the regional specific involvement of BDNF/TrkB in hippocampal-independent conditioned taste aversion（CTA） memory *** Real time PCR and ELISA were respectively used to detect the BDNF mRNA and protein changes at various time points after CTA *** phosphorylation levels normalized to total TrkB were measured by immunoprecipitation and *** was used to detect role of endogenous BDNF on CTA memory *** We found region-specific changes in BDNF expression during CTA *** conditioning induced increased BDNF levels in the central nuclei of amygdala （CeA） and insular cortex,but not in the basolateral amygdala（BLA） and ventromedial prefrontal ***, we found that the enhanced TrkB phosphorylation occurred at the time point before the increased BDNF expression, suggesting rapid induction of activity-dependent BDNF secretion by CTA ***,targeted infusion of BDNF antibodies or BDNF antisense oligonucleotides revealed that activity-dependent BDNF secretion and synthesis in the CeA,but not the BLA,was respectively involved in the short- and long-term memory formation of ***, we found that infusion of exogenous BDNF into the CeA could enhance CTA *** These data suggest that region-specific BDNF release and synthesis temporally regulate different CTA memory phases through activation of TrkB receptors.

关键词： brain derived neurotrophic factor（BDNF） amygdale secretion synthesis short term memory（STM） long term memory（LTM）

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APPLl mediates synaptic NMDA receptor-dependent neuroprotection

APPLl mediates synaptic NMDA receptor-dependent neuroprotect...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Yu-Bin WANG~1,Shuang QIU~1,Jie-Jie WANG,Shao-Hua WANG,Jian-Hong LUO~* Department of Neurobiology,Zhejiang University School of Medicine,Hangzhou 310058,China

N-methy1-D-aspartate(NMDA) receptors are glutamate gated ion channels and play important roles in both physiology and pathophysiology of central *** activation of NMDA receptor can cause neuronal loss in acute trauma such as ischemia,as well as certain neurodegenerative diseases such as Huntington's disease. However,physiological levels of synaptic NMDA receptor activity can promote neuronal survival through different signaling pathways under different *** them,PI3K(phosphoinositide-3-kinase)/Akt kinase cascade is a key signaling pathway responsible for neuroprotective effects of NMDA receptor *** is still unknown how NMDA receptors are coupled with PI3K-Akt ***1(adaptor protein containing pH domain,PTB domain,and Leucine zipper motif),is an endosomal adaptor protein which are associated with various transmembrane ***,APPL1 has been reported to interact with,and regulate the activity of,the kinase *** the present study,using biochemical analysis and immunostaining,we found that APPL1 associates with NMDA receptor complex through its C-terminal PDZ binding *** importantly,APPL1 is involved in synaptic NMDA receptor mediated neuroprotective *** of APPLl-NMDA receptor complex interaction by peptide against APPL1 C-terminal PDZ binding motif blocks activation of Akt by synaptic NMDA receptor,and also blocks NMDA receptor-dependent neuroprotection from starve-induced *** suggests that in central nervous system APPL1, as an adaptor protein,connects synaptic NMDA receptor with intracellular PI3K/Akt cascade and down-stream prosurvival signaling pathway.

关键词： APPLl NMDA receptor Akt neuroprotection

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Regulation of histone acetylation during consolidation of CPA extiction in vmPFC

Regulation of histone acetylation during consolidation of CP...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Wei-Sheng WANG~1,Shuo KANG~1,Wen-Tao LIU~2,Mu LI~1,Yao LIU~1,Chuan YU~1,Jing-Gen LIU~(1,*) 1 State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences, Shanghai 201203,China 2 School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210046,China

The drug-associated conditioned stimulus(CSs) come to influence drug-seeking and relapse behaviour through the memories they *** animals undergo extinction training(no drug) will decrease response rates and extinction entails new learning rather than *** the model of conditioned place aversion(CPA) of acute morphine-dependent rats,we found that lesions of ventral medial prefrontal cortex(vmPFC) impaired the consolidation of extinction of *** addition,we found that both extracellular signal-regulated kinases(ERK) pathway and histone acetylation in vmPFC are involved in consolidation of extinction and also found that Trichostatin A,a histone deacetylase(HDAC) inhibitor,can facilitate the extinction of *** further found that manipulation of vmPFC ERK activity by its antagonist U0126 and agonist D-cycloserine not only differentially influenced the behavior of CPA rats but also altered histone ***,we found that extinction of CPA increased BDNF exonⅠbut not exonⅣin the vmPFC,We further found that the increasement is accompanied by a significant increase in histone H3 acetylation and pCREB around the BDNF exon I gene *** also found that inhibition of trk B by intra-vmPFC injections of K252a significantly disrupted the consolidation of ***,our findings suggest that histone acetylation is mediated by ERK pathway and the increasement of BDNF protein expression in vmPFC are required for the consolidation of CPA extinction and the tyrosine kinase inhibitor K252a prevented the consolidation of CPA.

关键词： extinction vmPFC ERK histone acetylation BDNF

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Approaching the channelopathies associated with epilepsy by natural sodium channel-specific modulators

Approaching the channelopathies associated with epilepsy by ...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Yong-Hua JI Lab Neuropharmacol.NeurotoxicoL,Shanghai University,Shanghai 200444,China

＜正＞Voltage-gated sodium channel plays an indispensable role in the initiation and propagation of the action *** of sodium channel properities are associated with several neurological pathogenetic disorders such as epilepsy,movement disorder,ataxia,inherited pain and so *** drugs such as phenytoin,carbamazepine, lamotrigine and sodium valproate targeting on sodium channels have been widely applied in clinical antiepileptic therapies *** thus study,unique sodium channel site3/4-specific modulators from Asian scorpion Buthus martemi Karsch（BmK） were investigated to have capabilities of either kindling convulsant or anticonvulsant effects on the animal *** was found that sodium channel site3-specific modulators named as BmK I and BmKαIV can induce strong epileptic behaviors and epileptiform discharges in the *** hippocampal c-Fos expression was elicited,and the inactivation of sodium currents in hippocampal neurons was significantly prolonged by BmK *** addition,BmK I and BmKαIV promoted the release of endogenous glutamate and intrasynaptosomal free calcium and sodium *** channel site4-specific modulators such as BmK IT2 and BmK AS exhibited anticonvulsant effects on PTZ and pilocarpine-induced seizures,and reduced the persistent currents of hippocampal ***,BmK AS did not affect the epileptiform EEG in the pilocarpine model over the same dose range in PTZ-induced model,though it did increase the latency to status epilepticus onset and significantly reduced the seizure ***,BmK I and BmKαIV may be used as ideal tools to gain a better understanding of epileptogenesis associated with sodium *** AS and BmK IT2 may serve as novel probes in exploring the role of different sodium channel subtypes in epileptogenic setting and as potential candidates in developing antiepileptic drugs targeting on specific sodium channel subtypes.

关键词： epilepsy sodium channels sodium channel site3/4-specific modulators

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EEG DMN:Where is the light?

EEG DMN:Where is the light?

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Andrew CN CHEN Kung WANG Center for Higher Brain Functions Capital Medical University

＜正＞Objective EEG default mode network（DMN） at rest was reported with specific regional spectral field powers（Chen et al.,Neuroimage 2008）.This study was aimed at determining the effects of respective light and dark condition on EEG *** Subjects were healthy young adults,aged 20-26 yrs,recorded with 128-ch EEG in 4 respective sessions:Eyes-open with strong light（EO/sl）,eyes-open with complete dark（EO/cd）,eyes-closed with strong light（EC/sl）,and eyes-closed with complete dark（EC/cd）.The spectral EEG of 7 broad-bands were quantified in regional field power at each *** was conducted in Two Way RM *** All band powers, except alpha-1 and alpha-2,showed no significant *** alpha-1 of anterior and parietal region,EO was much less than EC（F=7.88,F＜0.0015） and Complete Dark was much higher than Strong Light condition（F=8.39,P＜0.012）. In alpha-2 of post-parietal region,there was an interaction effect（F=5.25,P＜0.039）.The Strong Light induced much less power than Complete Dark in EO condition,but no change in EC *** EO modulates alpha-1 and alpha-2 EEG powers than those in EC *** under Complete Dark condition,EO modulates the alpha-1 and alpha-2 ***,light has much less to do with the EEG alpha effect than the motor act of EO from EC. Significance This study poses an interesting question on the EEG DMN of blind *** theory would predicl higher alpha powers in blind persons than those in sighted persons.

关键词： EEG DMN eyes-open eyes-closed strong light complete dark

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Protection and its mechanisms of OECs on adult rat injured retinal ganglion cells

Protection and its mechanisms of OECs on adult rat injured r...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Tao WANG,Ming-Mei WU,Si-Wei YOU Institute of Neurosciences,The Fourth Military Medical University,Xi'an 710032,China

Transplantation of olfactory ensheathing cells(OECs) becomes one of the promising strategies in restoring lost functions of injured central nervous *** was revealed that OECs transplanted into partially injured spinal cord have a distant in vivo neuroprotective effect on descending cortical and brain stem ***,this study gave no answers to the question whether OECs can protect the central sensitive neurons with a closer axonal injury because different neurons respond variously to similar axonal injury and the distance between the neuronal soma and axonal injury site has a definite effect on the severity of neuronal response and *** the present study,we investigated the effect of transplanted OECs on axotomized retinal ganglion cells(RGCs) after intra-orbital optic nerve (ON) transection in adult rats and possible in vitro *** fluorescent protein-OECs were injected into the ocular stumps of transected ON and a significantly higher number of surviving RGCs was found together with a consistent remarked increase in the mRNA and protein levels of BDNF within the ON stump and retina in OEC-treated group at 7,but not 2 and 14,day time point when compared to the control ***,the effects of BDNF neutralization on the neuroprotection of adult OEC-conditioned medium(OEC-CM) on scratch-insulted RGCs were examined in *** results showed that OEC-CM protected cultured RGCs from scratch insult,and neutralization of BDNF by BDNF neutralizing antibody attenuated such neuroprotection of the *** findings suggest that OEC transplantation induces the expression of BDNF in the ocular ON stump and retina and delay the death of axotomized RGCs at a certain survival *** factors including BDNF secreted by OECs can protect injured OECs in vitro and BDNF plays a major role in such a protection of OECs.

关键词： olfactory ensheathing cells retinal ganglion cell optic nerve conditioned medium

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Antidepressant citalopram inhibits delayed rectifier outward K+ current in mouse cortical neurons

Antidepressant citalopram inhibits delayed rectifier outward...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Xiao-Qin ZHAN,Yan-Lin HE,Jin-Jing YAO,Jia-Li ZHUANG,Yan-Ai MEI Institutes of Brain Science,School of Life Sciences and State Key Laboratory of Medical Neurobiology,Fudan University,Shanghai 200433,China

Citalopram,a selective serotonin reuptake inhibitor（SSRI）,as well as an antidepressant,is thought to exert its effects by increasing synaptic serotonin（5-HT）***,few studies have addressed the possibility that citalopram has other molecular mechanisms of *** examined the effects of citalopram on delayed rectifier outward K current（I）in mouse cortical *** citalopram reversibly inhibited I in a dose-dependent manner and significantly shifted both steady-state activation and inactivation curves towards hyperpolarization *** 5-HT itself nor antagonists of 5-HT and dopamine receptors could abolish citalopram-induced inhibition of *** addition,intracellular application of GTPy-S similarly failed to prevent the inhibition of I by *** applied intracellularly,citalopram had no effect on I and also did not influence the reduction of I induced by extracellular *** effect of citalopram was use-dependent,but not frequency-dependent,and did not require channel *** recordings in acute prepared cortical slice showed that citalopram significantly reduced the action potential（AP）firing frequency of cortical neurons and increased action potential duration（APD）.The selective Kv2.1 subunit blocker Jingzhaotoxin-Ⅲ（JZTX-Ⅲ）did not abolish citalopram-induced I *** of HEK293 cells with Kv2.1 or Kv2.2 constructs indicated that citalopram mainly inhibited Kv2.2 *** together,we suggest that citalopram-induced inhibition of Iin mouse cortical neurons is independent of G-protein coupled receptors,and might exert its antidepressant effects by enhancing presynaptic *** results may help to explain some of the unknown therapeutic effects on antidepressant of citalopram.

关键词： citalopram antidepressant IK mouse cortical neurons action potential

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