The NMDA receptor complex - a signalling hub at the origin of cognitive flex-ibility?

The NMDA receptor (NMDAR) is one of the most thoroughly investigated receptors in the mammalian brain. It plays an important role in learning and memory and NMDAR hypofunction or pharmacological NMDAR inhibition leads to impairments in cognitive flexibility. However, the mechanistic underpin-nings of its role for cognitive flexibility and consequently the possibilities to exploit, expand or mobi-lise neural resource associated with its function are rather poorly investigated and developed so far. Research has staggered here at least in part for two reasons, the lack of behavioural paradigms that are sophisticated and sensitive enough to unmask underlying behavioural processes and the lack of knowledge about the NMDAR signalling hub. This hub extends beyond the receptor complex itself and its interactome in the sense that endogenous modulators and eventually glial signalling components are part of it. The aim of our project is to unravel the contribution of the NMDAR signalling hub to cog-nitive flexibility. We will focus our analysis on subregions of the frontal cortex involved in cognitive flexibility. We will combine a sophisticated behavioural paradigm in mice (attentional set shifting) with state-of-the-art, highly sensitive proteome analyses deciphering molecular, cellular and network properties of cognitive flexibility. In particular, the effect of age, environmental and cognitive enrich-ment, and circadian strain on the NMDAR signalling hub will be assessed with the aim to identify key players in the different subregions of the frontal cortex. This will enable us to identify druggable targets and corresponding intervention strategies. Our hypothesis is that a specific modulation of those com-ponents of the NMDAR signalling hub that are associated - both on a group and individual level - with stronger cognitive flexibility can be used as a neural resource. Consequently, pharmacological inventions specifically targeting these components should efficiently improve impaired cognitive flexi-bility and thereby improve cognitive functioning in general.