Reciprocal molecular and cellular cholinergic working memory impairments in Alzheimer's disease model mice

The degeneration of basal forebrain cholinergic neurons is a key pathophysiological feature of Alzheimer's disease (AD). These cholinergic neurons target cortical neurons including those in the granular retrosplenial cortex (RSG) to facilitate essential cognitive functions. At the cellular level, acetylcholine supports working memory by inducing persistent firing that outlasts the stimulus, but how such cholinergic-induced persistent firing is altered in AD remains unknown.

Using multiscale molecular and cellular analyses, we investigated neuron type-specific transcriptomic and physiological impairments of cholinergic persistent signaling in the RSG of 5xFAD mice.

Cholinergic inputs to RSG were reduced in 5xFAD mice. Expression of the Chrm1 gene encoding M1 muscarinic receptors was also reduced in RSG neurons, coupled with impaired cellular persistent firing.

The loss of M1 receptors suggests that allosteric M1 modulators being considered for treatment of AD symptoms may not be as effective on key cell types, necessitating further multiscale investigation.