Brain-Derived Neurotrophic Factor Val66Met Genotype Modulates Latent Inhibition: Relevance for Schizophrenia.

Abstract

Latent inhibition (LI) is a measure of selective attention and learning relevant to Schizophrenia (SZ), with 2 abnormality poles: Disrupted LI in acute SZ, thought to underlie positive symptoms, and persistent LI (PLI) in schizotypy and chronic SZ under conditions where normal participants fail to show LI. We hypothesized that Brain-Derived Neurotrophic Factor (BDNF)-Met genotype shifts LI toward the PLI pole. We investigated the role of BDNF-Val66Met polymorphism and neural activation in regions involved in LI in mice, and the interaction between the BDNF and CHL1, a gene associated with SZ. No LI differences occurred between BDNF-wild-type (WT) (Val/Val) and knock-in (KI) (Met/Met) mice after weak conditioning. Chronic stress or stronger conditioning disrupted LI in WT but not KI mice. Behavior correlated with activation in infralimbic and orbitofrontal cortices, and nucleus accumbens. Examination of LI in CHL1-KO mice revealed no LI with no Met alleles (BDNF-WTs), PLI in CHL1-WT mice with 1 Met allele (BDNF-HETs), and PLI in both CHL1-WTs and CHL1-KOs with 2 Met alleles (BDNF-KIs), suggesting a shift to LI persistence with the number of BDNF-Met alleles in the CHL1 model of acute SZ. Results support a role for BDNF polymorphisms in gene-gene and gene-environment interactions relevant to SZ. BDNF-Met allele may reduce expression of some acute SZ symptoms, and may increase expression of negative symptoms in individuals with chronic SZ. Evaluation of (screening for) SZ phenotypes associated with mutations at a particular locus (eg, CHL1), may be masked by strong effects at different loci (eg, BDNF).