Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: relevance to schizophrenia

Abstract

Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D1 receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia. The animal could provide valuable insights into phenotypic aspects of this psychiatric disorder.

Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia

“…These observations suggest that a new homeostatic state involving dysregulated phospho-stimulator/repressor sites could result in a higher efficiency of SNARE complex association n schizophrenia (Figure 5). Notably, the findings are convergent with ‘blind-drunk’ and Munc18-1-overexpressing mice models, both displaying enhanced SNARE interactions and schizophrenia-related behaviors (38; 39). It remains uncertain whether or not the antipsychotic-induced amelioration of the schizophrenia-like endophenotypes in these murine models is mediated by normalization of the intrinsically elevated SNARE protein-protein interactions.…”

“…Mutant mice showed higher vulnerability to a prenatal stress-induced schizophrenia-like syndrome, a behavioral manifestation that was abolished with antipsychotic treatment (38). More recently, transgenic mice overexpressing the accessory protein Munc18-1 were found to mimic structural and functional abnormalities present in schizophrenia patients, as well as showing enhanced dopamine release and behavioral activation with amphetamine (39). Conversely, impairment of SNARE proteins’ capacity to form complexes was associated with cognitive decline and progression of Alzheimer’s disease in a community-based aging study (40; 41), regardless of the amounts of Stx1 and SNAP25 present.…”

Munc18-1 redistributes in nerve terminals in an activity- and PKC-dependent manner

“…Deletion of munc18-1 completely arrests synaptic transmission , whereas increased Munc18-1 levels result in a larger readily releasable vesicle pool (RRP) and increased synaptic efficacy (Toonen et al, 2006b). Mutations in munc18-1 are found in patients with epilepsy and intellectual disability, and Munc18-1 dysregulation is implicated in Alzheimer's disease and schizophrenia (Jacobs et al, 2006;Saitsu et al, 2008;Hamdan et al, 2009;Milh et al, 2011;Vatta et al, 2012;Mastrangelo et al, 2013;Urigüen et al, 2013). Hence, Munc18-1 is required for normal brain function and its global expression levels scale with synaptic strength.…”

Cytokine pathway disruption in a mouse model of schizophrenia induced by Munc18-1a overexpression in the brain

“…As previously described [27], the overexpression of Munc18-1a in mice resulted in a successful replication of several behavioral, neurochemical and morphological features associated with schizophrenia. Here we show that in addition to this, the Munc18-OE mice exhibit a neuroinflammatory pattern that is similar to the one reported in the genuine disease.…”

“…Munc18-OE mice were generated as previously described by pronuclear microinjection [27]. WT mice (National Institute for Agronomic Research, Madrid, Spain) used as controls displayed the same background.…”