title: Brain-derived neurotrophic factor genotype impacts the prenatal cocaine-induced mouse phenotype.
abstract: Prenatal cocaine exposure leads to persistent alterations in the growth factor brain-derived neurotrophic factor (BDNF), particularly in the medial prefrontal cortex (mPFC) and hippocampus, brain regions important in cognitive functioning. BDNF plays an important role in the strengthening of existing synaptic connections as well as in the formation of new contacts during learning. A single nucleotide polymorphism in the BDNF gene (Val66Met), leading to a Met substitution for Val at codon 66 in the prodomain, is common in human populations, with an allele frequency of 20-30% in Caucasians. To study the interaction between prenatal cocaine exposure and BDNF, we have utilized a line of BDNF Val66Met transgenic mice on a Swiss Webster background in which BDNF(Met) is endogenously expressed. Examination of baseline levels of mature BDNF protein in the mPFC of prenatally cocaine-treated wild-type (Val66Val) and Val66Met mice revealed significantly lower levels compared to prenatally saline-treated mice. In contrast, in the hippocampus of prenatally saline- and cocaine-treated adult Val66Met mice, there were significantly lower levels of mature BDNF protein compared to Val66Val mice. In extinction of a conditioned fear, we found that prenatally cocaine-treated Val66Met mice had a deficit in recall of extinction. Examination of mature BDNF protein levels immediately after the test for extinction recall revealed lower levels in the mPFC of prenatally cocaine-treated Val66Met mice compared to saline-treated mice. However, 2 h after the extinction test, there was increased BDNF exons I, IV, and IX mRNA expression in the prelimbic cortex of the mPFC in the prenatally cocaine-treated BDNF Val66Met mice compared to prenatally saline-treated mice. Taken together, our results suggest the possibility that prenatal cocaine-induced constitutive alterations in BDNF mRNA and protein expression in the mPFC differentially poises animals for alterations in behaviorally induced gene activation, which are interactive with BDNF genotype and differentially impact those behaviors. Such findings in our prenatal cocaine mouse model suggest a gene X environment interaction of potential clinical relevance.
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Zeeba D
authors.initials: ZD
authors.lastname: Kabir
authors.forename: Frederico
authors.initials: F
authors.lastname: Lourenco
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Byrne
authors.forename: Aaron
authors.initials: A
authors.lastname: Katzman
authors.forename: Francis
authors.initials: F
authors.lastname: Lee
authors.forename: Anjali M
authors.initials: AM
authors.lastname: Rajadhyaksha
authors.forename: Barry E
authors.initials: BE
authors.lastname: Kosofsky
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D005260:Female; D005787:Gene Frequency / Q000187:drug effects; D005838:Genotype; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine