Elevated expression of endogenous glial cell line?derived neurotrophic factor impairs spatial memory performance and raises inhibitory tone in the hippocampus

Parvalbumin-positive interneurons (PV+) are a key component of inhibitory networks in the brain and known to modulate memory learning by shaping network activity. The mechanisms PV+ neuron generation maintenance not fully understood, yet current evidence suggests that signalling via glial cell line-derived neurotrophic factor (GDNF) receptor GFR?1 positively modulates migration differentiation cortex. Whether GDNF also regulates cells hippocampus is currently unknown. In this study, we utilized Gdnf “hypermorph” mouse model where overexpressed from native gene locus, providing greatly increased spatial temporal specificity protein expression over established models ectopic expression. Gdnfwt/hyper mice demonstrated impairments long-term performance Morris water maze test an increase tone measured electrophysiologically acute slice preparations. Increased number was confirmed immunohistochemically discrete cortical areas epileptic seizure threshold observed vivo. data consolidate prior for actions as regulator development cortex demonstrate functional effects upon excitability modulation GABAergic under challenge.