Abstract
The presynaptic protein RIM1α mediates multiple forms of presynaptic plasticity at both excitatory and inhibitory synapses. Previous studies of mice lacking RIM1α (RIM1α−/− throughout the brain showed that deletion of RIM1α results in multiple behavioral abnormalities. In an effort to begin to delineate the brain regions in which RIM1 deletion mediates these abnormal behaviors, we used conditional (floxed) RIM1 knockout mice (fRIM1). By crossing these fRIM1 mice to previously characterized transgenic cre lines, we aimed to delete RIM1 selectively in the dentate gyrus (DG), using a specific preproopiomelanocortin promoter driving cre recombinase (POMC-cre) line , and in pyramidal neurons of the CA3 region of hippocampus, using the kainate receptor subunit 1 promoter driving cre recombinase (KA-cre). Neither of these cre driver lines was uniquely selective to the targeted regions. In spite of this, we were able to reproduce a subset of the global RIM1α−/− behavioral abnormalities, thereby narrowing the brain regions in which loss of RIM1 is sufficient to produce these behavioral differences. Most interestingly, hypersensitivity to the pyschotomimetic MK-801 was shown in mice lacking RIM1 selectively in the DG, arcuate nucleus of the hypothalamus and select cerebellar neurons, implicating novel brain regions and neuronal subtypes in this behavior.
Highlights
In mice, global deletion of presynaptic proteins often results in significant behavioral abnormalities reminiscent of human cognitive disease, though an understanding of brain regions or cell types mediating such phenotypes are not clear
IHC staining for yellow flourescent protein (YFP) in the Floxed RIM1 (fRIM1)/POMC-cre+/R26RYFP mice showed successful cre-mediated recombination largely limited to the dentate gyrus (DG) granule neurons, select neurons in the granule and molecular layers of the cerebellum, and arcuate nucleus of the hypothalamus (Figure 1a–c)
Consistent with cre-mediated recombination data, we found RIM1 transcripts to be decreased by 43.89% in the DG (SEM = ±7.48%, P < 0.05) and 24.39% in the cerebellum (SEM = ±8.97%, P < 0.05) in fRIM1/POMC-cre+ mice compared with controls
Summary
Global deletion of presynaptic proteins often results in significant behavioral abnormalities reminiscent of human cognitive disease, though an understanding of brain regions or cell types mediating such phenotypes are not clear. Post-mortem studies on schizophrenic brains have consistently found alterations in presynaptic proteins, genes involved in GABAergic neurotransmission, in the cerebellum, hippocampus and cortex (Akbarian and Huang 2006; Eastwood et al 2001; Glantz & Lewis 1997; Guidotti et al 2000; Sawada et al 2005; Tamminga et al 2004; Woo et al 2004). We have found that deletion of the presynaptic protein Rab3a interacting molecule 1α (RIM1α) in mice induced significant behavioral abnormalities, including some schizophrenia-relevant phenotypes, though RIM1α has not been directly implicated in human schizophrenia. Our findings suggest that loss of RIM1 in other brain regions or in multiple brain regions simultaneously may partially reproduce other behavioral abnormalities observed in RIM1α−/− mice
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