Coloboma hyperactive mutant mice exhibit regional and transmitter-specific deficits in neurotransmission.
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, KCl-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.
Raber
J
J
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California, USA.
Mehta
P P
PP
Kreifeldt
M
M
Parsons
L H
LH
Weiss
F
F
Bloom
F E
FE
Wilson
M C
MC
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000502:physiology; D003103:Coloboma / Q000235:genetics* / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006948:Hyperkinesis / Q000235:genetics* / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics* / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D014018:Tissue Distribution
D018377:Neurotransmitter Agents; D001127:Arginine Vasopressin; D012701:Serotonin; D018698:Glutamic Acid; D011189:Potassium Chloride; D003346:Corticotropin-Releasing Hormone; D000109:Acetylcholine; D002118:Calcium; D004298:Dopamine