Background
Knock-in mice with the common human brain-derived neurotrophic factor (BDNF) Val66Met
polymorphism have impaired trafficking of BDNF messenger RNA to dendrites. It was
hypothesized, given evidence that local synapse formation is dependent on dendritic
translation of BDNF messenger RNA, that loss-of-function Met allele mice would show
synaptic deficits both at baseline and in response to ketamine, an N-methyl-D-aspartate antagonist that stimulates synaptogenesis in prefrontal cortex
(PFC).
Methods
Whole-cell recordings from layer V medial PFC pyramidal cells in brain slices were
combined with two-photon laser scanning for analysis of wildtype, Val/Met, and Met/Met
mice both at baseline and in response to a low dose of ketamine.
Results
Val/Met and Met/Met mice were found to have constitutive atrophy of distal apical
dendrites and decrements in apically targeted excitatory postsynaptic currents in
layer V pyramidal cells of PFC. In addition, spine density and diameter were decreased,
indicative of impaired synaptic formation/maturation (synaptogenesis). In Met/Met
mice the synaptogenic effect of ketamine was markedly impaired, consistent with the
idea that synaptogenesis is dependent on dendritic translation/release of BDNF. In
parallel behavioral studies, we found that the antidepressant response to ketamine
in the forced swim test was blocked in Met/Met mice.
Conclusions
The results demonstrate that expression of the BDNF Met allele in mice results in
basal synaptic deficits and blocks synaptogenic and antidepressant actions of ketamine
in PFC, suggesting that the therapeutic response to this drug might be attenuated
or blocked in depressed patients who carry the loss of function Met allele.
Key Words
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Article info
Publication history
Published online: October 31, 2011
Accepted:
September 28,
2011
Received in revised form:
September 27,
2011
Received:
August 11,
2011
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
