Pharmacological interrogation of TrkA-mediated mechanisms in hippocampal-dependent memory consolidation

In the brain, the TrkA receptor for Nerve Growth Factor (NGF) is expressed primarily in the cholinergic system. TrkA/NGF support neuronal health and function, and deficiencies in this axis are associated with progressive cholinergic neuron atrophy and death, and with cognitive deficit in disorders such as Down’s syndrome and Alzheimer’s disease. These observations led to the hypothesis that TrkA agonists may rescue atrophic cholinergic neurons and benefit cognition. Indeed, a small molecule TrkA partial agonist called D3 normalized TrkA signals and improved memory in cognitive impairment models of ageing and an APP mouse model of Alzheimer’s disease. Paradoxically, in young healthy mice chronic delivery of D3 caused impaired memory without impairing learning, a form of anterograde amnesia. Here, we use this as a model to study the mechanisms of impaired memory. In young healthy mice acute or chronic treatment with D3 induces hyperactivation of TrkA-mediated signals in hippocampus, and causes a deficit in hippocampal-dependent memory consolidation proximal to drug exposure, without affecting learning or memory retrieval. The impairment after acute drug exposure is reversible. The impairment after long-term drug exposure is irreversible, likely due to a decrease in hippocampal CA1 neuron basal arborization. These findings support the notion of a homeostatic role for TrkA in memory, and demonstrate the differential outcomes of TrkA (hyper)activation in healthy versus disease states.在大脑中，神经生长因子（Nerve Growth Factor, NGF）的TrkA受体主要表达于胆碱能系统。TrkA与NGF共同维持神经元的健康与功能，该信号轴的功能缺陷与进行性胆碱能神经元萎缩、死亡以及唐氏综合征、阿尔茨海默病等疾病中的认知缺陷密切相关。上述研究观察结果催生了“TrkA激动剂可挽救萎缩的胆碱能神经元并改善认知”这一假说。事实上，一种名为D3的小分子TrkA部分激动剂可使TrkA信号恢复正常，并在衰老相关认知障碍模型与阿尔茨海默病APP小鼠模型中改善小鼠记忆。令人意外的是，在年轻健康小鼠中，长期给予D3会导致记忆损伤但不影响学习，该现象属于顺行性遗忘症。本研究以此为模型，探究记忆损伤的潜在机制。研究发现，在年轻健康小鼠中，急性或慢性给予D3会诱导海马体中TrkA介导的信号通路过度激活，并在给药后短期内造成海马依赖型记忆巩固缺陷，但不影响学习与记忆提取。急性给药后的记忆损伤是可逆的，而长期给药后的损伤则不可逆，这可能与海马CA1神经元基础树突分支减少有关。上述研究结果证实了TrkA在记忆过程中的稳态调控作用，并揭示了健康状态与疾病状态下，TrkA（过度）激活所产生的不同结局。