Coloboma Hyperactive Mutant Mice Exhibit Regional and Transmitter‐Specific Deficits in Neurotransmission

Abstract

The mouse mutant coloboma (Cm/+), which exhibits profound spontaneous hyperactivity and bears a deletion mutation on chromosome 2, including the gene encoding synaptosomal protein SNAP‐25, has been proposed to model aspects of attention‐deficit hyperactivity disorder. Increasing evidence suggests a crucial role for SNAP‐25 in the release of both classical neurotransmitters and neuropeptides. In the present study, we compared the release of specific neurotransmitters in vitro from synaptosomes and slices of selected brain regions from Cm/+ mice with that of +/+ mice. The release of dopamine (DA) and serotonin (5‐HT) from striatum, and of arginine vasopressin and corticotropin‐releasing factor from hypothalamus and amygdala is calcium‐dependent. Glutamate release from and content in cortical synaptosomes of Cm/+ mice are greatly reduced, which might contribute to the learning deficits in these mutants. In dorsal striatum of Cm/+ mutants, but not ventral striatum, KCI‐induced release of DA is completely blocked and that of 5‐HT is significantly attenuated, suggesting that striatal DA and 5‐HT deficiencies may be involved in hyperactivity. Further, although acetylcholine failed to induce hypothalamic corticotropin‐releasing factor release from Cm/+ slices, restraint stress increased plasma corticosterone levels in Cm/+ mice to a significantly higher level than in +/+ mice, suggesting an important role for arginine vasopressin in hypothalamic‐pituitary‐adrenal axis activation. These results suggest that reduced SNAP‐25 expression may contribute to a region‐specific and neurotransmitter‐specific deficiency in neurotransmitter release.

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

“…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.…”

“…First, SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release. 12,13 Second, postmortem studies have shown modifica-tions of SNAP25 protein levels in some brain regions of bipolar patients. 14,15 Third, SNAP25 gene has been widely associated with attention-deficit hyperactivity disorder (ADHD), which is known to share genetic susceptibility with early-onset BD.…”

Animal models of attention deficit/hyperactivity disorder (ADHD): a critical review

“…The SNAP-25 protein is essential for the fusion of the neurotransmitter vesicle with the presynaptic membrane in order to release neurotransmitters. This might explain why the DA release in the dorsal striatum of the coloboma mutant mouse is almost completely lost (Raber et al 1997). In addition, the D 2 receptor expression is increased in the ventral tegmental area and substantia nigra (Jones et al 2001b).…”

Polymorphism in SNAP29 gene promoter region associated with schizophrenia

“…8 Fourth, deletion of SNAP25 is responsible for the behavioral alterations found in coloboma mice, an animal model of ADHD. [9][10][11] The clinical features of ADHD overlap with the symptoms of mania and hypomania. Finally, a decrease in SNAP-25 and synaptophysin proteins has been found in the brains of schizophrenics.…”