Semaphorin-dependent GABAergic synapse formation: A novel approach to increasing inhibition in the intact brain
Semaphorin-dependent GABAergic synapse formation: A novel approach to increasing inhibition in the intact brain
批准号:
10119391
负责人:
SUZANNE PARADIS
金额:
$58.77万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-08-01 至 2021-04-30
关键词:
AcuteAddressAdultBenzodiazepinesBiologicalBostonBrainCD100 antigenCell surfaceCollaborationsDataDevelopmentDiazepamDrug TargetingElectric StimulationElectrophysiology (science)EpilepsyEpileptogenesisEventExtracellular DomainFDA approvedFutureGlutamatesGoalsHippocampus (Brain)HumanIn VitroIndividualInfusion proceduresInhibitory SynapseIntravenousIntravenous infusion proceduresLaboratoriesMethodsModelingMolecularMusNeonatalNeuronsPatientsPediatric HospitalsPentylenetetrazolePharmaceutical PreparationsProteinsRefractoryRiskRodentRodent ModelSeizuresSemaphorinsSignal PathwaySignal TransductionSliceSodium ChannelStatus EpilepticusSynapsesTechniquesTechnologyTertiary Protein StructureTestingTherapeuticTimeVirusWorkbasedensityimprovedin vivoin vivo Modelinduced pluripotent stem cellintravenous injectionmortalitymouse modelneural circuitnovelnovel strategiesnovel therapeuticsoptimal treatmentsplexinpre-clinicalprenatalpreventreceptorreceptor functionrelating to nervous systemresponsesmall moleculesuccesssynaptogenesistraffickingtreatment strategy
中文摘要
摘要
我们建议利用Sema4D信号的突触生成潜力来增加GABA能突触
数字,从而加强对神经回路的抑制和抑制癫痫发作。这种方法可能是
有利于防止癫痫的形成、阻止其进展或抑制过度兴奋
在一次癫痫发作中。
之前,我的实验室发现分泌蛋白Semaphorin 4D(Sema4D)驱动抑制性突触
在培养的海马神经元和脑片上以非常快的时间尺度(即分钟)形成
出生前和新生儿的海马体。我们还证明了海马区内注入的
Sema4D的胞外区进入成年海马区迅速促进新的
GABA能突触。重要的是,这些数据表明,分子机制调节
幼年海马区的GABA能突触发生在成人仍有功能,这一机制
可以被利用来调节网络兴奋性。我们直接解决了这一点,证明了
Sema4D治疗可预防由直接电刺激海马区或由
静脉输注致惊厥药物戊四唑。此外,我们发现Sema4D治疗
恢复了地西潘在难治性癫痫持续状态啮齿动物模型中的疗效。
鉴于这些研究的成功,我的实验室承担了一个新的实验方向,以确定
Sema4D治疗对人类癫痫具有治疗潜力。我们将把工作重点放在可译性上
Sema4D是一种治疗癫痫持续状态(SE)的抗癫痫药物。不幸的是,大约
30%的SE患者对包括苯二氮类药物在内的现有药物治疗无效。一
关于癫痫持续状态难治性起源的假说是延长神经去极化导致
使细胞表面GABAA受体内化,从而减少对
GABA能信号(Joshi&Kapur,2012)。我们假设,通过大幅增加
使用Sema4D治疗抑制性突触,我们可以维持或重新建立苯二氮类药物
这些人大脑中的敏感性。第二,为了进一步我们在体内的小鼠研究
Sema4D依赖的癫痫抑制,为了进一步解释我们的发现,我们将探索
给小鼠注射Sema4D的替代方法(例如,静脉注射编码Sema4D的病毒)。
最后,我们将通过询问Sema4D是否促进啮齿类动物来测试我们的发现在啮齿类动物中的可译性
人类神经元中的抑制性突触形成。
英文摘要
SUMMARY
We propose to harness the synaptogenic potential of Sema4D signaling to increase GABAergic synapse
number, thus enhancing inhibition in neural circuits and suppressing seizures. This approach could be
beneficial to preventing the establishment of epilepsy, halting its progression, or suppressing hyperexcitability
during a seizure event.
Previously my lab discovered that the secreted protein Semaphorin 4D (Sema4D) drives inhibitory synapse
formation on a remarkably fast time scale (i.e. minutes) in hippocampal neurons and slice cultured from the
pre-natal and neonatal hippocampus. We also demonstrated that intra-hippocampal infusion of the
extracellular domain of Sema4D into the adult hippocampus rapidly promotes the formation of new
GABAergic synapses. Importantly, these data demonstrate that the molecular machinery regulating
GABAergic synaptogenesis in the young hippocampus remains functional in the adult and that this machinery
can be harnessed to modulate network excitability. We directly addressed this point by demonstrating that
Sema4D treatment protects against seizures induced by direct electrical stimulation of the hippocampus or by
intravenous infusion of the proconvulsant drug pentylenetetrazol. Further, we found that Sema4D treatment
restored the efficacy of diazepam in a rodent model of refractory status epilepticus.
Given the success of these studies, my laboratory has undertaken a new experimental direction to determine if
Sema4D treatment has therapeutic potential for human epilepsies. We will focus our work on the translatability
of Sema4D as an anti-seizure therapeutic for treating status epilepticus (SE). Unfortunately, approximately
30% of patients with SE are refractory to treatment with current medications including benzodiazepines. One
hypothesis about the origin of refractoriness in status epilepticus is that prolonged neural depolarization leads
to internalization of cell-surface GABAA receptors, thus reducing total inhibitory current in response to
GABAergic signaling (Joshi & Kapur, 2012). We hypothesize that by acutely increasing the number of
inhibitory synapses using Sema4D treatment, we could maintain or re-establish benzodiazepine
sensitivity in the brains of these individuals. Second, in order to further our in vivo mouse studies of
Sema4D-dependent seizure suppression, and to further the translatability of our findings, we will explore
alternative methods of administering Sema4D (e.g. intravenous injection of virus encoding Sema4D) to mice.
Lastly, we will test the translatability of our findings with Sema4D in rodents by asking if Sema4D promotes
inhibitory synapse formation in human neurons.
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专著(0)
科研奖励(0)
会议论文
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海外基金