Abstract
Reduced brain-derived neurotrophic factor (BDNF) signaling has been shown in the frontal cortex and hippocampus in schizophrenia. The aim of the present study was to investigate whether a BDNF deficit would modulate effects of chronic cannabis intake, a well-described risk factor for schizophrenia development. BDNF heterozygous mice (HET) and wild-type controls were chronically treated during weeks 6, 7, and 8 of life with the cannabinoid receptor agonist, CP55,940 (CP). After a 2-week delay, there were no CP-induced deficits in any of the groups in short-term spatial memory in a Y-maze task or novel object recognition memory. Baseline prepulse inhibition (PPI) was lower but average startle was increased in BDNF HET compared to wild-type controls. Acute CP administration before the PPI session caused a marked increase in PPI in male HET mice pre-treated with CP but not in any of the other male groups. In females, there were small increases of PPI in all groups upon acute CP administration. Acute CP administration furthermore reduced startle and this effect was greater in HET mice irrespective of chronic CP pre-treatment. Analysis of the levels of [3H]CP55,940 binding by autoradiography revealed a significant increase in the nucleus accumbens of male BDNF HET mice previously treated with CP but not in any of the other groups or in the caudate nucleus. These results show that BDNF deficiency and chronic young-adult cannabinoid receptor stimulation do not interact in this model on learning and memory later in life. In contrast, male “two hit” mice, but not females, were hypersensitive to the effect of acute CP on sensorimotor gating. These effects may be related to a selective increase of [3H]CP55,940 binding in the nucleus accumbens, reflecting up-regulation of CB1 receptor density in this region. These data could be of relevance to our understanding of differential “two hit” neurodevelopmental mechanisms in schizophrenia.
Highlights
It is becoming widely accepted that the development of schizophrenia cannot be explained by single gene mutations or environmental factors
There were four male and four female experimental groups: wild-type mice treated with vehicle (WT/veh), wild-type mice treated with CP55,940 (WT/CP), Brain-derived neurotrophic factor (BDNF) heterozygous mice treated with vehicle (HET/veh) and BDNF HET mice treated with CP55,940 (HET/CP)
Two-Way analysis of variance (ANOVA) split by sex revealed that male HET mice weighed more compared to male wild-type mice [main effect of genotype: F(1, 49) = 8.2; P = 0.006] and CP-treated animals had lower bodyweight compared to vehicle-treated mice independent of genotype [main effect of CP treatment: F(1, 49) = 10.7; P = 0.002]
Summary
It is becoming widely accepted that the development of schizophrenia cannot be explained by single gene mutations or environmental factors. Several animal model studies are attempting to delineate the molecular mechanisms involved in this synergism, with the ultimate aim to provide new treatment targets, including for early intervention. Studies have shown that temporary treatment with low doses of antipsychotics in late adolescence may be effective in preventing the emergence of schizophrenia-like behavioral phenotype in neurodevelopmental animal models of the illness (Piontkewitz et al, 2009). Post-mortem studies have found significant reductions of BDNF gene expression and protein levels in the brains of people with schizophrenia (Hashimoto et al, 2003; Weickert et al, 2003; Durany and Thome, 2004). Corticosterone treatment in BDNF heterozygous (HET) mice caused sex-specific long-term effects in the Y-maze and other effects (Klug et al, 2012)
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