Interaction between environmental and genetic factors modulates schizophrenic endophenotypes in the Snap-25 mouse mutant blind-drunk

Abstract

To understand the pathophysiology of neuropsychiatric disorders such as schizophrenia requires consideration of multiple genetic and non-genetic factors. However, very little is known about the consequences of combining models of synaptic dysfunction with controlled environmental manipulations. Therefore, to generate new insights into gene–environment interactions and complex behaviour, we examined the influence of variable prenatal stress (PNS) on two mouse lines with mutations in synaptosomal-associated protein of 25 kDa (Snap-25): the blind-drunk (Bdr) point mutant and heterozygous Snap-25 knockout mice. Neonatal development was analysed in addition to an assessment of adult behavioural phenotypes relevant to the psychotic, cognitive and negative aspects of schizophrenia. These data show that PNS influenced specific anxiety-related behaviour in all animals. In addition, sensorimotor gating deficits previously noted in Bdr mutants were markedly enhanced by PNS; significantly, these effects could be reversed with the application of anti-psychotic drugs. Moreover, social interaction abnormalities were observed only in Bdr animals from stressed dams but not in wild-type littermates or mutants from non-stressed mothers. These results show for the first time that combining a synaptic mouse point mutant with a controlled prenatal stressor paradigm produces both modified and previously unseen phenotypes, generating new insights into the interactions between genetics and the environment relevant to the study of psychiatric disease.

A Novel Mechanism and Treatment Target for Presynaptic Abnormalities in Specific Striatal Regions in Schizophrenia

“…This change in amino-acid sequence in SNAP-25 results in a greater affinity for the partner SNARE protein syntaxin, greater stability of the SNARE complex, and decreased exocytosis in glutamatergic terminals (Jeans et al, 2007). Interestingly, in the blind-drunk mouse, PPI abnormalities in adulthood are further enhanced if the mice are exposed to prenatal stress (Oliver and Davies, 2009). Treatment of blind-drunk mice with clozapine restored PPI to near normal levels; haloperidol was also moderately effective (Oliver and Davies, 2009).…”

“…Interestingly, in the blind-drunk mouse, PPI abnormalities in adulthood are further enhanced if the mice are exposed to prenatal stress (Oliver and Davies, 2009). Treatment of blind-drunk mice with clozapine restored PPI to near normal levels; haloperidol was also moderately effective (Oliver and Davies, 2009). Interestingly, earlier studies of rat brain slice preparations found that administration of dopamine increased SNARE complex formation, an effect that could be blocked by haloperidol (Fisher and Braun, 2000).…”

Strengths and limitations of genetic models of ADHD

“…Further studies are necessary to investigate the role of SNAP-25 in ADHD, but with regard to animal models it would be preferable to have a model of selective SNAP-25 deficiency such as SNAP-25 heterozygous mice. It should be noted, however, that recent study involving SNAP-25 heterozygous mice failed to detect significant hyperactivity or any other behavioral abnormalities in SNAP-25 heterozygous mice and thus the phenotype of Coloboma mice is likely caused by the deficiency in other genes disrupted in this strain (Oliver and Davies 2009). …”

Linking Stress and Schizophrenia: A Focus on Prepulse Inhibition

“…As the focus of this chapter lies on the effects of stress on PPI, we will not discuss the neurochemical findings from genetic animal models of schizophrenia. Genotypes that have been found to interact with early stress to influence PPI include, nuclear receptor Nurr1 heterozygosity (i.e., 12 weeks of isolation rearing - Eells et al, 2006), Snap-25 mouse mutant blind-drunk (i.e., variable prenatal stress - Oliver & Davies, 2009), and NMDA receptor hypofunction mouse mutant (predation stress - Duncan et al, 2004). Notably, the latter study made use of predator olfactory cues (i.e., rat odor), which normalized the reduced PPI that was observed under control conditions in male mutants only.…”