Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer’s disease models

Background Cognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examine electrophysiological evidence for active compensation in Alzheimer’s disease (AD) focusing on the cholinergic signalling pathways in the prefrontal cortex. These pathways are vulnerable to neuropathology in AD and its preclinical models and are essential for attention and executive function. Methods We functionally interrogate aspects of the cholinergic system ex vivo , in brain slices of prefrontal cortex from two preclinical models: a compound transgenic AD mouse that permits optogenetically-triggered release of endogenous acetylcholine and a transgenic AD rat that closely recapitulates the human trajectory of AD. We then tested the impact of therapeutic interventions to further amplify the compensated responses and preserve the typical kinetic profile of cholinergic signaling. Results In two AD models, we find a potentially-compensatory upregulation of functional cholinergic responses above non-transgenic controls after onset of pathology. To identify the locus of this enhanced cholinergic signal, we dissect key pre- and post-synaptic components with pharmacological strategies. We identify a significant and selective increase in post-synaptic nicotinic receptor signalling on prefrontal cortical neurons. To probe the additional impact of therapeutic intervention on the adapted circuit, we test cholinergic and nicotinic-selective pro-cognitive treatments. The inhibition of acetylcholinesterase further enhances endogenous cholinergic responses but greatly distorts their kinetics. Positive allosteric modulation of nicotinic receptors, by contrast, enhances endogenous cholinergic responses and retains their rapid kinetics. Conclusions We demonstrate that functional nicotinic compensation occurs within the prefrontal cortex in two AD models. Promisingly, this compensated nicotinic signal can be boosted while preserving its rapid kinetic signature. Taken together, we conclude that compensatory mechanisms act within the prefrontal cholinergic pathway and reveal a new approach for cognitive treatment in AD neuropathology. ### Competing Interest Statement The authors have declared no competing interest. * ACh : acetylcholine AD : Alzheimer’s Disease ChAT : choline acetyl transferase ChR2 : channelrhodopsin DHβE : dihydro-β-erythroidine gal : galantamine hz : hertz ms : millisecond mV : millivolt nTg : non-transgenic opto-Ach : optogenetic release of acetylcholine pA : pico-ampere PAM : positive allosteric modulator prl : prelimbic Tg : transgenic