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

衰老海马CA3回路的高兴奋性：进展、后果和机制***海马对认知和记忆至关重要，衰老与海马记忆功能下降有关。最近的研究表明，海马CA3回路的功能改变与认知衰老的个体间差异密切相关。特别是，低剂量的左乙拉西坦（一种抗癫痫药物）治疗已被证明可以改善患有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，总的来说，老化CA3神经元的细胞和网络活动尚不清楚。***我的研究目的是检查啮齿动物模型的海马网络活动。我们最近的研究表明，与成年小鼠（3-6个月）相比，老龄小鼠（18-20/24-28个月）的海马/CA3活动异常兴奋。我们的数据显示，在54%的衰老/衰老小鼠中，海马脑电图（EEG）出现异常，但在成年小鼠中很少出现异常，老年小鼠海马切片中CA3兴奋场电位比成年小鼠更频繁，与成年小鼠相比，老年小鼠CA3锥体神经元的节律性IPSCs更弱，静息膜电位更阳性，突发放电率更高。***我们将结合神经生理和行为评估来检验三个假设。1)海马CA3电路可能在一定比例的衰老/衰老小鼠中容易出现高兴奋性，而作为CA3高兴奋性的体内指标的海马脑电图异常峰可能在个体小鼠中由于海马老化而进展。2) CA3高兴奋性可中断老年小鼠海马计算功能，这与海马记忆衰退密切相关；因此，恢复CA3回路的兴奋-抑制平衡或减少异常海马脑电图峰的实验操作可能改善老年小鼠海马记忆功能。3)老年小鼠CA3高兴奋性可能有多种因素，包括gaba能抑制减弱、谷氨酸能兴奋增强和/或CA3锥体神经元固有兴奋性改变。本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. *****