Novel rat behavioural and (opto) pharmacological approaches to investigate alpha7 nicotinic acetylcholine receptors in relation to neuropsychiatric disorder endophenotypes – NICOPTOTOUCH

Cognitive deficits are a core and shared syndrome of various neurodevelopmental, neurodegenerative and psychiatric disorders. Numerous studies have shown an implication of the homomeric nicotinic acetylcholine receptors composed of the alpha7 subunit (a7*nAChRs) in these disorders. Notably, frequent human specific genetic variations of the gene encoding alpha7 have been associated with these pathologies. These receptors are largely expressed in several brain areas that are important for cognitive functioning, such as the hippocampus and the prefrontal cortex, and alterations in their expression levels have been observed in these regions in neurocognitive patients. a7*nAChRs represent a therapeutic target of hope but new investigations are now needed to better understand their role in cognitive processes and to propose novel pharmacological tools to modulate them. We propose to characterize, in the rat, the role of these receptors, notably those expressed in the hippocampus and the prefrontal cortex, and the impact of their genetic variations, in a set of cognitive processes commonly impaired in several brain disorders, using the touchscreen technology. This approach will allow us, for the first time in preclinical research, to evaluate the role of a7*nAChRs in these processes in a manner very similar to the way they are tested in humans. Moreover, we will develop photocontrollable a7*nAChRs, which will allow us to antagonize them at different specific time-points of cognitive testing thanks an unprecedented temporal resolution. On parallel, we will develop a7*nAChR highly selective nanobodies, screened for their silent (SAM) or positive (PAM) allosteric modulator properties. SAM nanobodies will be used to optimize the photocontrollable a7*nAChRs, while the PAM nanobodies will be assessed for their precognitive properties on the touchscreen tasks in our rat models, in comparison with already available molecules. This project should bring significant advances into the undertstanding of the role of a7*nAChRs in the cognitive deficits associated with a number of brain disorders, and should provide a solid basis for the design of novel therapeutical trials based on these receptors.