The Effects of Neuronal Calcium Sensor-1 Deletion on Mouse Behaviour and Neurophysiology

While neuronal calcium sensor-1 (NCS-1) has been implicated in neurotransmitter release, synaptic plasticity, spatial cognition and a number of diseases, its role in mammalian behaviour, learning and motivation have not been thoroughly explored. Here we investigated the effects of Ncs-1 deletion on mouse behaviour and explored potential underlying physiological mechanisms. Since NCS-1 is a dopamine-receptor interacting protein and has known roles in hippocampal synaptic plasticity, we focused on striatal-dependent motivated behaviours as well as hippocampal-dependent learning and memory. We hypothesized Ncs-1 deletion would (1) impair motivated behaviour and decrease striatal dopamine signalling, (2) disrupt spatial learning and memory as well as hippocampal synaptic plasticity, and (3) produce endophenotypes of human neuropsychiatric disease. We found Ncs-1 knockout (Ncs-1-/-) mice were less willing to work for food than wildtype mice in operant conditioning tasks with high work requirements or when a less-preferred food was freely available. However, Ncs-1-/- mice preferred sweet foods as much as wildtype mice and showed intact Pavlovian incentive learning, operant acquisition and habit formation. At the level of striatal physiology, Ncs-1-/- mice displayed a 50% decrease in electrically evoked dopamine release from the nucleus accumbens core in acute slices. Dopamine half-life, dopamine receptor D2 (DRD2) levels, and dopamine transporter (DAT) levels were relatively unaffected. Learning and memory was also relatively intact. Ncs-1-/- mice showed normal spatial reference memory, fear memory, and spontaneous object recognition, but were impaired in displaced object recognition. Subtle changes were found in hippocampal electrophysiology, with a trend for less metabotropic glutamate receptor (mGluR)-dependent LTD early on and reduced maintenance of LTP in the dentate gyrus. Ncs-1-/- mice had wildtype levels of locomotion, amphetamine-induced hyperlocomotion, sensorimotor gating, and anxiety-like behaviour but showed decreased social approach without impairments to actual social interaction behaviour. Our results suggest NCS-1 has a role in modulating effort to approach and work toward goals and rewards, via effects on presynaptic dopamine release.Ph.D