Chemogenetic manipulation of learning-tagged neurons is sufficient to rescue progressive memory deficits in a mouse model of Alzheimer's disease

INTRODUCTION: Alzheimer's disease (AD) primarily affects episodic memory, which relies on the medial temporal lobe, including the hippocampus and lateral entorhinal cortex (LEC). However, it remains unclear whether memory deficits in AD reflect disrupted encoding of new experiences or impaired retrieval of previously stored information. METHODS: APPJ20 transgenic mice were used to investigate memory deficits. Neuronal populations activated during the learning phase of associative and non-associative tasks were tagged to express the excitatory chemogenetic receptor hM3Dq. Chemogenetic activation of these tagged neurons was performed during the recall phase of the tasks. RESULTS: Chemogenetic reactivation of LEC or dentate gyrus (DG) learning-tagged neurons rescued memory performance in associative and non-associative tasks, respectively. Neuronal activation, assessed using c-Fos as a marker, revealed a specific deficit in the reactivation of neurons recruited during learning. DISCUSSION: Chemogenetic reactivation of neuronal ensembles in the LEC and DG restored memory performance, suggesting that memory deficits in APPJ20 mice are associated with a failure in the endogenous reactivation of learning-relevant neurons. HIGHLIGHTS: APPJ20 mice exhibited early entorhinal synaptic dysfunction and impaired episodic-like memory retrieval. At a later stage, hippocampal synaptic function became impaired, leading to altered non-associative memory performance. The analysis of neuronal activation using c-Fos revealed a specific impairment of the subpopulation recruited during memory encoding. Chemogenetic reactivation of LEC learning-tagged neurons rescued associative memory performance in 2-month-old APPJ20 mice, while promoting dendritic spine maturation and stabilization in LEC neurons. Chemogenetic reactivation of DG learning-tagged neurons in 6-month-old APPJ20 mice restored non-associative memory retrieval. This study supports the hypothesis that during AD progression, memory is encoded but not accessible through natural cues alone.