Hyperexcitability of aging hippocampal CA3 circuitry: progression, consequences and mechanisms

老化海马 CA3 回路的过度兴奋：进展、后果和机制

• 批准号: RGPIN-2015-04153
• 负责人: Zhang, Liang
• 金额: $ 2.91万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=687782
• 关键词: Hyperexcitability; aging; hippocampal; CA3; circuitry

Hyperexcitability of aging hippocampal CA3 circuitry: progression, consequences and mechanisms ***        The hippocampus is crucial for cognition and memory, and aging is associated with a decline in hippocampal memory functions. Recent studies suggest that functional alterations of the hippocampal CA3 circuitry are strongly associated with inter-individual differences in cognitive aging. In particular, treatments with low-dose levetiracetam (an antiepileptic drug) have been shown to improve hippocampal memories in aged humans with mild cognitive impairments and in aged rats or mice. However, overall the cellular and network activities of aged CA3 neurons are not well understood. ***        My research is aimed to examine hippocampal network activities in rodent models. Our recent studies suggest hyperexcitable hippocampal/CA3 activities in aging/aged mice (18-20/24-28 months) relative to adult mice (3-6 months). Our data reveal aberrant hippocampal electroencephalographic (EEG) spikes in 54% of aging/aged mice but only rarely in adult mice, more frequent CA3 excitatory field potentials in hippocampal slices of aged mice than in the slices of adult mice, and weaker rhythmic IPSCs, more positive resting membrane potentials and higher rates of burst firing in the CA3 pyramidal neurons of aged mice as compared to the CA3 pyramidal neurons of adult mice. ***        We will test three hypotheses using a combination of neurophysiological and behavioral assessments. 1) The hippocampal CA3 circuitry may be prone to hyperexcitability in a proportion of aging/aged mice and that aberrant hippocampal EEG spikes as an in vivo indicator of such CA3 hyperexcitability may progress in individual mice as a result of hippocampal aging. 2) CA3 hyperexcitability may interrupt the hippocampal computational functions, which correlate strongly with hippocampal memory decline in aged mice; therefore, experimental manipulations that restore the excitation-inhibition balance of the CA3 circuitry or decrease the aberrant hippocampal EEG spikes may improve hippocampal memory functions in aged mice. 3) Multiple factors may contribute to CA3 hyperexcitability, including attenuated GABAergic inhibition, enhanced glutamatergic excitation and/or altered intrinsic excitability of the CA3 pyramidal neurons in aged mice. Data from this proposed study may help to understand the fundamental physiology of hippocampal aging at both network and cellular levels, to promote healthy aging and to improve preventative approaches. *****

老化海马CA 3回路的过度兴奋：进展、后果和机制 * 海马体对认知和记忆至关重要，衰老与海马体记忆功能的下降有关。最近的研究表明，海马CA 3区电路的功能改变与认知老化的个体间差异密切相关。特别是，低剂量左乙拉西坦（一种抗癫痫药物）治疗已被证明可以改善轻度认知障碍的老年人和老年大鼠或小鼠的海马记忆。然而，总体而言，老年CA 3神经元的细胞和网络活动尚未得到很好的理解。 我的研究旨在研究啮齿动物模型中的海马网络活动。我们最近的研究表明，相对于成年小鼠（3-6个月），衰老/老年小鼠（18-20/24-28个月）的海马/CA 3活动过度兴奋。我们的数据揭示了54%的老龄/老年小鼠中异常的海马脑电图（EEG）尖峰，但在成年小鼠中很少，老年小鼠海马切片中的CA 3兴奋性场电位比成年小鼠切片中的更频繁，以及更弱的节律性IPSC，老年小鼠海马CA 3区锥体神经元静息膜电位阳性率和爆发性放电率高于老年小鼠海马CA 3区锥体神经元成年小鼠 ** 我们将使用神经生理学和行为评估的组合来测试三个假设。1)海马CA 3回路可能在一定比例的老化/老年小鼠中易于过度兴奋，并且作为这种CA 3过度兴奋的体内指标的异常海马EEG尖峰可能由于海马老化而在个体小鼠中进展。2)CA 3过度兴奋可中断海马计算功能，这与老年小鼠海马记忆衰退密切相关;因此，恢复CA 3回路的兴奋-抑制平衡或减少异常海马EEG尖峰的实验操作可改善老年小鼠海马记忆功能。3)多种因素可能导致CA 3过度兴奋，包括减弱GABA能抑制、增强海马能兴奋和/或改变老年小鼠CA 3锥体神经元的内在兴奋性。这项拟议研究的数据可能有助于在网络和细胞水平上了解海马衰老的基本生理学，促进健康衰老并改善预防方法。*****