Gene-environment interactions affect long-term depression (LTD) through changes in dopamine receptor affinity in Snap25 deficient mice.
Genes and environmental conditions interact in the development of cognitive capacities and each plays an important role in neuropsychiatric disorders such as attention deficit/hyperactivity disorder (ADHD) and schizophrenia. Multiple studies have indicated that the gene for the SNARE protein SNAP-25 is a candidate susceptibility gene for ADHD, as well as schizophrenia, while maternal smoking is a candidate environmental risk factor for ADHD. We utilized mice heterozygous for a Snap25 null allele and deficient in SNAP-25 expression to model genetic effects in combination with prenatal exposure to nicotine to explore genetic and environmental interactions in synaptic plasticity and behavior. We show that SNAP-25 deficient mice exposed to prenatal nicotine exhibit hyperactivity and deficits in social interaction. Using a high frequency stimulus electrophysiological paradigm for long-term depression (LTD) induction, we examined the roles of dopaminergic D2 receptors (D2Rs) and cannabinoid CB1 receptors (CB1Rs), both critical for LTD induction in the striatum. We found that prenatal exposure to nicotine in Snap25 heterozygote null mice produced a deficit in the D2R-dependent induction of LTD, although CB1R regulation of plasticity was not impaired. We also show that prenatal nicotine exposure altered the affinity and/or receptor coupling of D2Rs, but not the number of these receptors in heterozygote null Snap25 mutants. These results refine the observations made in the coloboma mouse mutant, a proposed mouse model of ADHD, and illustrate how gene×environmental influences can interact to perturb neural functions that regulate behavior.
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico, 87131, USA; Sandia National Laboratories, Albuquerque, New Mexico, 87185, USA.
Michael
M
Baca
Andrea M
AM
Allan
L Donald
LD
Partridge
Michael C
MC
Wilson
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D005260:Female; D059647:Gene-Environment Interaction; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009538:Nicotine / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics
D043884:Receptor, Cannabinoid, CB1; D011954:Receptors, Dopamine; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D009538:Nicotine
Cannabinoid CB1 receptors (CB1Rs); Dopaminergic D2 receptors (D2Rs); Long-term depression (LTD); Prenatal nicotine exposure; SNAP-25; Short-term depression (STD)