Behavioural Brain Research 197 (2009) 435–441 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report Behavioral characterization of dysbindin-1 deficient sandy mice Sanjeev K. Bhardwaj, Moogeh Baharnoori, Bahram Sharif-Askari, Aarthi Kamath, Sylvain Williams, Lalit K. Srivastava ∗ Douglas Mental Health University Institute, Department of Psychiatry, McGill University, 6875 LaSalle Boul, Montreal H4H 1R3, QC, Canada article info Article history: Received 11 July 2008 Received in revised form 9 September 2008 Accepted 7 October 2008 Available online 15 October 2008 Keywords: Dysbindin-1 Schizophrenia Animal model Habituation Amphetamine sensitization Fear conditioning Recognition memory Nociception abstract Dysbindin-1 (dystrobrevin binding protein-1) has been reported as a candidate gene associated with schizophrenia. Dysbindin-1 mRNA and protein levels are significantly reduced in the prefrontal cortex and hippocampus of schizophrenia subjects. To understand the in-vivo functions of dysbindin-1, we stud- ied schizophrenia relevant behaviors in adult male Sandy homozygous (sdy/sdy) and heterozygous (sdy/+) mice that have a natural mutation in dysbindin-1 gene (on a DBA/2J background) resulting in loss of protein expression. Spontaneous locomotor activity of sdy/sdy and sdy/+ mice in novel environment was not sig- nificantly different from DBA/2J controls. However, on repeated testing in the same environment for 7 days, sdy/sdy mice, in contrast to DBA/2J controls showed a lack of locomotor habituation. Locomotor activat- ing effect of a low dose of d-amphetamine (2.5 mg/kg ip), a behavioral measure of mesolimbic dopamine activity, was significantly reduced in the mutant mice. Interestingly, sdy/sdy mice showed enhanced loco- motor sensitization to repeated five daily injection of amphetamine. Possible cognitive impairment in Sandy mutants was revealed in novel object recognition test as sdy/sdy and sdy/+ mice spent significantly less time exploring novel objects compared to DBA/2J. Sdy/sdy mice also showed deficits in emotionally motivated learning and memory showing greater freezing response to auditory conditioned stimulus (CS) in fear conditioning paradigm. In thermal nociceptive test, the latency of paw withdrawal in sdy/sdy and sdy/+ animals was significantly higher compared to DBA/2J indicating hypoalgesia in the mutants. Taken together, these data suggest that dysbindin-1 gene deficiency leads to significant changes in cognition and altered responses to psychostimulants. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Dysbindin-1 (dystrobrevin binding protein-1, DTNBP-1), is a coiled-coil protein encoded by DTNBP1 gene located on chromo- some 6p22.3 in humans and was first reported to be associated with increased risk of schizophrenia in Irish population [1]. Although many subsequent studies have shown the association of dysbindin gene variations to schizophrenia in diverse populations [2–6], there are still debates about the true nature of association [7–9]. Stud- ies indicate the association of dysbindin-1 with prefrontal brain functions in normal individuals [10] and with spatial working memory performance [11], intellectual decline [12], negative symp- toms [13] and decrease in general cognitive abilities [14,15] in schizophrenia patients. The precise functions of dysbindin protein are unknown, but it is widely expressed in rodent and human brain [16,17] and thought to be involved in signaling at both pre- and post-synaptic sites, with particularly prominent expression at glu- ∗ Corresponding author. Tel.: +1 514 761 6131x2936; fax: +1 514 762 3034. E-mail address: lalit.srivastava@mcgill.ca (L.K. Srivastava). tamatergic synapses [18,19]. Reductions in both mRNA and protein levels of dysbindin have been reported in the prefrontal cortex and the hippocampus of schizophrenia post-mortem brains [18,20,21]. In the brain, dysbindin (352 amino acid, ∼50 kD, protein) binds to both  and -dystrobrevin, a member of the Dystrobrevin Protein Complex (DPC), which has been implicated in synaptic structures and signalling [16,22]. Dysbindin is also a member of Biogene- sis of Lysosome-related Organelle Complex-1 (BLOC-1), a protein complex that is involved in vesicle trafficking [22] and dendritic branching [23], and is reported to interact with several other mem- bers of this complex such as pallidin, muted and snapin [24]. Dysbindin is suggested to function as regulator of neurotrans- mitter vesicle exocytosis and vesicle biogenesis in endocrine cells and neurons [25]. Functionally, it has been shown that a reduction of dysbindin-1 can lower basal and stimulus-induced glutamate release, whereas over-expression of dysbindin elevates glutamate release in cultured neurons [26]. For another neurotransmitter, suppression of dysbindin in PC12 cells leads to the increase in dopamine (DA) release [27] and decreased tissue DA and high DA turnover has been shown in dysbindin deficient Sandy mouse [28]. Dysbindin may also play a role in DA receptor trafficking as shown 0166-4328/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2008.10.011