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

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Latent inhibition (LI) measures selective attention and learning, with abnormalities linked to schizophrenia (SZ).
• Two poles of LI abnormality exist: disrupted LI in acute SZ and persistent LI (PLI) in chronic SZ and schizotypy.
• The Brain-Derived Neurotrophic Factor (BDNF)-Met genotype was hypothesized to shift LI towards the PLI pole.

Purpose of the Study:

• To investigate the role of the BDNF-Val66Met polymorphism in LI.
• To examine neural activation in brain regions associated with LI.
• To explore the interaction between BDNF and CHL1 genes in a mouse model relevant to SZ.

Main Methods:

• Investigated BDNF-Val66Met polymorphism and neural activation in mice.
• Utilized knockout (KO) and wild-type (WT) mouse models for BDNF and CHL1 genes.
• Assessed LI under varying conditioning strengths and chronic stress conditions.

Main Results:

• BDNF-Met genotype (KI mice) showed resistance to LI disruption under stress or strong conditioning, unlike WT mice.
• LI patterns correlated with neural activation in the infralimbic cortex, orbitofrontal cortex, and nucleus accumbens.
• In CHL1-KO mice, LI was absent in BDNF-WTs, showed PLI in BDNF-HETs, and PLI in BDNF-KIs, indicating a dose-dependent effect of BDNF-Met alleles.

Conclusions:

• BDNF polymorphisms play a role in gene-gene and gene-environment interactions relevant to SZ.
• The BDNF-Met allele may modulate acute SZ positive symptoms and potentially exacerbate negative symptoms in chronic SZ.
• Genetic screening for SZ phenotypes needs to consider potential masking effects from strong genetic influences at other loci, such as BDNF.