Impaired behavioural flexibility and memory in mice lacking GDNF family receptor alpha2.

The glial cell line-derived neurotrophic factor (GDNF) family receptor GFRalpha2 is the binding receptor for neurturin (NRTN). The main biological responses of GFRalpha2 are mediated via the Ret receptor tyrosine kinase, although it may also signal independently of Ret via the neural cell adhesion molecule NCAM. GFRalpha2 is expressed in many neurons of both the central and peripheral nervous system. Mice lacking GFRalpha2 receptors do not exhibit any gross defects in the central nervous system structure. However, they display profound deficits in the parasympathetic and enteric nervous system, accompanied by significant reduction in body weight after weaning. Here we present the results of behavioural analysis of the GFRalpha2-knockout mice. The knockout mice did not differ from wild-type mice in basic tests of motor and exploratory activity. However, differences were established in several memory tasks. The knockout mice were not impaired in the acquisition of spatial escape strategy. However, the deficit in flexibility in establishing a new strategy was revealed during reversal learning with the platform in the opposite quadrant of the pool. Furthermore, the knockout mice displayed significant impairment in contextual fear conditioning and conditioned taste aversion tests of memory. The results suggest that GFRalpha2 signalling plays a role in the development or maintenance of cognitive abilities that help in solving complex learning tasks.