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Choline acetyltransferase neurons in the vertical diagonal band of Broca (vChATs) degenerate in the early stage of Alzheimer’s disease (AD). Here, we report that vChATs directly innervate newly generated immature neurons (NGIs) in the dorsal hippocampus (dNGIs) of adult mice and regulate both the dNGIs survival and spatial pattern separation. In a mouse model that exhibits amyloid-β plaques similar to AD patients, cholinergic synaptic transmission, dNGI survival and spatial pattern separation are impaired. Activation of vChATs with theta burst stimulation (TBS) that alleviates the decay in cholinergic synaptic transmission effectively protects against spatial pattern separation impairments in the AD mice and this protection was completely abolished by inhibiting the dNGIs survival. Thus, the impairments of pattern separation-associated spatial memory in AD mice are in part caused by degeneration of cholinergic synaptic transmission that modulates the dNGIs survival.

Figure 1. vChATs directly innervate dNGIs.

To map the specific neuronal cells that develop synaptic connections with vChATs in adult mice, the authors used a genetically modified Cre-dependent anterograde monosynaptic tracing system. They demonstrated that vChATs directly innervate newly generated immature neurons (NGIs) in the dorsal zone of the hippocampus (dNGIs) of adult mice. In AD mice, cholinergic synaptic transmission is impaired and this impairment contributes to the loss of pattern separation-dependent spatial memory.

 
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