Richter-Levin G, Segal M
Department of Psychology, University of Haifa, Israel.
Rev Neurosci. 1996 Apr-Jun;7(2):103-13. doi: 10.1515/revneuro.1996.7.2.103.
The cholinergic hypothesis of senile dementia /18/ does not provide a sufficient explanation for age-dependent spatial learning deficits; these are observed before an appreciable reduction of cholinergic markers can be detected. Behavioral deficits similar to those observed in old rats cannot be induced in young rats by comparable cholinergic lesions but do occur following combined cholinergic/serotonergic lesions. Serotonergic raphe grafts in the hippocampus (but not in the entorhinal cortex or hypothalamus) prevent such combined lesion-induced spatial learning deficits. The behavioral deficits are associated with a reduction of hippocampal commissure feed-forward inhibition. Similar reduced inhibition is found in old rats, deficient in their performance of a spatial learning water-maze task. Finally, treating old rats with the serotonergic precursor 5-hydroxytryptophan (5-HTP) reduces the age-dependent spatial learning deficits and restores hippocampal commissure feed-forward inhibition. Serotonin may act in parallel to the cholinergic innervation of the hippocampus by affecting inhibitory interneurons but in addition it may act by modulating acetylcholine release. Acetylcholine release is modulated by serotonin and the enhancing effects of serotonin releasing drugs on dentate granule cell excitability are mediated by acetylcholine. We thus propose that a reduction of serotonergic modulation of hippocampal interneuron activity and impaired modulation of cholinergic effects in the hippocampus contribute to age-dependent cognitive deficits.
老年痴呆症的胆碱能假说/18/并不能充分解释与年龄相关的空间学习缺陷；这些缺陷在可检测到胆碱能标志物明显减少之前就已被观察到。在年轻大鼠中，类似胆碱能损伤并不能诱发与老年大鼠中观察到的行为缺陷，但在胆碱能/5-羟色胺能联合损伤后确实会出现。海马体（而非内嗅皮质或下丘脑）中的5-羟色胺能中缝核移植可预防此类联合损伤诱导的空间学习缺陷。行为缺陷与海马连合前馈抑制的减少有关。在空间学习水迷宫任务表现不佳的老年大鼠中也发现了类似的抑制减少。最后，用5-羟色胺能前体5-羟色氨酸（5-HTP）治疗老年大鼠可减少与年龄相关的空间学习缺陷，并恢复海马连合前馈抑制。5-羟色胺可能通过影响抑制性中间神经元与海马体的胆碱能神经支配并行发挥作用，但此外它可能通过调节乙酰胆碱释放来发挥作用。乙酰胆碱释放受5-羟色胺调节，5-羟色胺释放药物对齿状颗粒细胞兴奋性的增强作用由乙酰胆碱介导。因此，我们提出海马中间神经元活动的5-羟色胺能调节减少以及海马体中胆碱能效应的调节受损导致了与年龄相关的认知缺陷。
