Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background

Abstract

Sandy mice have a deletion mutation in the gene encoding dysbindin-1, Dtnbp1, with consequent reduction of the protein in heterozygotes and its loss in homozygotes. The sandy mouse thus serves as an animal model of dysbindin-1 function. As this protein is concentrated in synaptic tissue and affects transmitter release, it may affect neuronal processes that mediate behavior. To investigate the neurobehavioral effects of the Dtnbp1 mutation, we studied littermate sandy and wild-type controls on a C57BL/6J genetic background. The three animal groups were indistinguishable in their external physical characteristics, sensorimotor skills and indices of anxiety-like behaviors. In the open field, however, homozygous animals were hyperactive and appeared to show less habituation to the initially novel environment. In the Morris water maze, homozygous animals displayed clear deficits in spatial learning and memory with marginal deficits in visual association learning. Apart from the last mentioned deficits, these abnormalities are consistent with hippocampal dysfunction and in some cases with elevated dopaminergic transmission via D2 dopamine receptors. As similar deficits in spatial learning and memory have been found in schizophrenia, where decreased dysbindin-1 has been found in the hippocampus, the sandy mouse may also model certain aspects of cognition and behavior relevant to schizophrenia.

Figure 1. Open Field

(a) Total distance traveled during the two 5 minute sessions in meters (m) and (b) total time spent in the center of the open field during the two 5 minute sessions for wild-type (WT) (□), sdy/+ (), and sdy/sdy (■) mice. ** p < 0.001, *** p < 0.0001. The amount of time expected in the center field by chance (42s) is larger than the observed times.

Figure 2. Rotarod Performance

Improvement in the time animals managed to stay atop accelerating rotarod on the 5 sessions with 3 trials per session. Symbols indicate WT (■), sdy/+ (), and sdy/sdy () mice. No significant differences among groups were found.

Figure 3. Elevated Zero Maze

(a) Total distance in meters traveled during the 5 minute session and (b) total time spent in the open arms during the 5 minute session for WT (□), sdy/+ () and sdy/sdy mice (■). **Difference at p = 0.002

Figure 4. Morris Water Maze

(a) Escape latency (s) during visible and hidden platform for WT (■), sdy/+ (), and sdy/sdy () mice, (b) percentage of time spent in all quadrants during probe trial, (c) annulus crossings during probe trial soon after final hidden platform trial for WT (■), sdy/+ (), and sdy/sdy (□) mice, and (d) average swim speed during the probe trial for WT mice (■), sdy/+ (), and sdy/sdy mice (□).