Spontaneous locomotor hyperactivity in a mouse mutant with a deletion including the Snap gene on chromosome 2

Abstract

The gene encoding the synaptosomal-associated protein--25 kDa (SNAP-25) was mapped by analysis of somatic cell hybrids and an intersubspecies backcross to mouse Chromosome 2. To identify potential mutants for SNAP- 25, mice bearing mutations mapping to this region of Chromosome 2 were screened for Snap gene abnormalities. Mice heterozygous for the semidominant mutation coloboma (Cm/+) were identified that carried a deletion of Snap gene sequence. Analysis of genomic DNA revealed that the Snap gene dosage in Cm/+ mice was 50% lower than control littermates. Additionally, SNAP-25 mRNA and protein expression were 50% lower in coloboma mice than control littermates. The coloboma mouse phenotype is characterized by small eyes and head bobbing; in addition, we observed that these mice were extremely hyperactive with spontaneous locomotor activity exceeding three times control mouse activity. The localization of the genetic abnormality in coloboma mice using the Snap gene marker will provide a powerful tool for studying the biologic basis of locomotor hyperactivity.

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

“…These results are consistent with the significant increase in SNAP25 protein level previously reported in Brodmann's area 9 (dorsolateral prefrontal cortex) in patients with BD, 15 as cellular and animal studies showed that variations in mRNA levels of SNAP25 correspond to equivalent variation in protein levels. 32,33 The SNP4 is located between two AP-1 consensusbinding sequences in a region that contributes to the repression of the SNAP25 transcription by binding of POU4F2 (also called Brn-3b). 30,34 This protein is a member of the Pict-Oct-Unc (POU) transcription factor family that involved in the development of the mammalian nervous system and for which an overexpression results in a failure of SNAP25 activation and neurite outgrowth.…”

“…Interestingly, coloboma mice have a 2 cM deletion on chromosome 2, including the SNAP25 gene. 32 Raber et al 12 studied the release of several neurotransmitters in heterozygous mice (Cm/ þ ), expressing 50% of the SNAP25 protein level, and showed that depolarisation failed to induce dopamine release and induced significantly lower than normal amounts of serotonin from the dorsal striatum. These results were recently confirmed by Fortin et al, 43 who showed that SNAP25 was required for dopamine release from rat neurons in culture.…”

Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder

“…18 The synaptosomal-associated protein of molecular weight 25 kDa (SNAP-25) was implicated in ADHD by studies on the mouse mutant strain coloboma (Cm/þ ). This radiation-induced mutant strain displays spontaneous hyperactivity that is suppressed by dextroamphetamine 19 and has thus been proposed as an animal model for ADHD. 20 The coloboma strain is hemizygous for a 2-cM deletion encompassing multiple genes, including SNAP-25.…”

Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hyperactivity disorder

“…8 Other characteristics include head bobbing, prominent eye dysmorphology, and paroxysmal circling activity. 9 Expression of a transgene encoding SNAP-25 rescues the hyperactivity but not the head bobbing or ophthalmic deformation 10 suggesting that the SNAP-25 gene is responsible for the observed hyperactivity but that the other characteristics of coloboma are the result of other genes in this deleted region. The coloboma strain is also delayed in some developmental milestones-the righting reflex and bar holding, a task designed to measure motor coordination.…”