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

老化的海马区CA3回路的超兴奋性：进展、后果和机制。海马区对认知和记忆至关重要，而衰老与海马体记忆功能的下降有关。最近的研究表明，海马区CA3回路的功能改变与认知老化的个体差异密切相关。特别是，低剂量左乙拉西坦(一种抗癫痫药物)的治疗已经被证明可以改善患有轻度认知障碍的老年人以及老年大鼠的海马体记忆。然而，总的来说，衰老的CA3神经元的细胞和网络活动还没有被很好地了解。他说，我的研究旨在检测啮齿动物模型中的海马网络活动。我们最近的研究表明，与成年小鼠(3-6个月)相比，衰老/老龄小鼠(18-20/24-28个月)的海马/CA3活动过度兴奋。我们的数据显示，54%的衰老/老龄小鼠的海马区脑电(EEG)异常，但成年小鼠很少出现；老龄小鼠的海马片比成年小鼠的脑片更频繁地出现CA3兴奋场电位；与成年小鼠的CA3锥体神经元相比，老年小鼠的CA3锥体神经元的IPSCs更弱，静息膜电位更正，爆发放电率更高。1)在一定比例的衰老/老龄小鼠中，海马区CA3环路可能易于过度兴奋，而作为CA3区兴奋性的体内指标的异常的海马区脑电尖峰电位可能会随着海马区的老化而在个别小鼠中进展。2)CA3的过度兴奋性可能干扰了与老年小鼠海马记忆减退密切相关的海马区计算功能，因此，恢复CA3回路的兴奋-抑制平衡或降低异常的海马区EEG峰电位的实验操作可能改善老年小鼠的海马记忆功能。3)老年小鼠CA3区神经元的GABA能抑制减弱、谷氨酸能兴奋性增强和(或)改变CA3区锥体神经元的固有兴奋性等多种因素参与了CA3区兴奋性的变化。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区衰老的基本生理学，促进健康衰老，并改进预防方法。*****

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. *****