Can just one nucleotide make the difference between happy-go-lucky and ho-hum? A common point mutation in the brain-derived neurotrophic factor (BDNF) gene is associated with depression and anxiety disorders, according to several researchers. Now Chen et al. report increased anxiety-like behavior that is resistant to antidepressant treatment in mice carrying the mutated form of BDNF in a recent article in Science.
Approximately 20-30% of the Caucasian population carries a point mutation in the BDNF gene that results in a methionine (Met) substitution for valine (Val) at amino acid 66. The BDNFMet allele is not present in the mouse, so the authors used homologous recombination to generate mice with the human BDNFMet allele in the endogenous BDNF gene locus.
Most BDNF release is induced rather than constitutive. Brain lysates from BDNF+/Met, BDNFMet/Met and wild-type mice had similar levels of BDNF. However, depolarization-induced BDNF release was reduced in hippocampal neurons from BDNF+/Met and BDNFMet/Met relative to wild-type mice, suggesting that the BDNFMet allele compromises stimulated BDNF release.
People with the BDNFMet allele show reduced hippocampal volume relative to those with the wild-type BDNFVal allele. Similarly, BDNF+/Met and BDNFMet/Met mice showed reduced hippocampal volume and dendritic complexity relative to wild-type mice. Hippocampal volume and dendritic complexity were similar in BDNF+/Met, BDNFMet/Met and heterozygous BDNF knockout (BDNF+/-) mice, suggesting that alterations in BDNF release affect hippocampal morphology.
Fear-conditioned learning tests quantify the fearful freezing behavior of mice exposed to a tone that they have previously associated with a shock. Context-dependent fear conditioning, which relies upon the hippocampus, but not cue-dependent fear conditioning, which relies upon the amygdala, was reduced in BDNF+/Met, BDNFMet/Met and BDNF+/- relative to wild-type mice, consistent with the decline in hippocampal-dependent learning in people with the BDNFMet allele.
BDNFMet/Met and BDNF+/- mice were more 'anxious' than wild-type mice. In the open field test, anxious mice cling to the edges rather than venturing into the center of the testing arena. BDNFMet/Met and BDNF+/- mice spent less time in the center of the open field than did wild-type mice. The elevated plus maze exploits fears of heights and open spaces. BDNFMet/Met and BDNF+/- mice spent less time in the open arms of the elevated plus maze than did wild-type mice.
Anxiety-like behaviors in BDNFMet/Met and BDNF+/- mice were resistant to antidepressant treatment. Novelty-induced hypophagia tests explore the conflict between a desirable treat (sweet condensed milk) and an aversive environment (the center of an open field). Anxiety increases the latency to reach the treat. Latency to drink the condensed milk was increased in BDNFMet/Met and BDNF+/- relative to wild-type mice. Fluoxetine treatement decreased the latency to drink for wild-type mice, but had no effect on BDNFMet/Met or BDNF+/- mice.
These data suggest that BDNF is important in anxiety-like behavior and indicate that selective serotonin reuptake inhibitors do not compensate for its deficiency. Sixty percent of people prescribed antidepressants do not respond to them. The BDNFMet allele may therefore be a helpful clinical marker for antidepressant treatment resistance.