| Vol 7 n° 2 - New Psychiatric Classification based on Endophenotypes |
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1 3 6
Poster
Neuroimaging
the genetic effects of
brain-derived
neurotrophic factor on
human
hippocampus
Because genes exert their effects on complex phenotypes,
such as mental illness, through intermediary molecular
and physiological mechanisms, these “intermediate phe-
notypes” should have a simpler genetic architecture.This
should make it easier to detect the effects of specific
genetic variants. Intermediate phenotypes referable to
hippocampus have received attention because of its role
in neuropsychiatric disorders such as schizophrenia.
Promising intermediate phenotypes have included mea-
sures of episodic memory, hippocampal activation
assayed with functional magnetic resonace imaging
(fMRI), and hippocampal volume assayed with MRI,
among others. In addition to these relatively complex
intermediate phenotypes, each gene also has related phe-
notypic measures based on its function. For example, the
dopamine D2 receptor exerts its effects by modulating
intracellular cyclic adenosine monophosphate (cAMP)
levels and therefore one can study the functional effects
of mutations in the D2 gene by examining downstream
effects on cAMP levels. Thus, the impact of a specific
genetic variant in a gene can be studied at basic cellular
level, as well as at the systems level.
BDNF is an obvious candidate gene for hippocampal
function in humans because studies in animals have
shown BDNF to be a critical mediator of episodic mem-
ory. For example, BDNF plays an essential role in the
molecular mechanisms of both early and late phases of
long-term potentiation (LTP) through both presynaptic
and postsynaptic mechanisms. To exert these effects,
BDNF is packaged and transported to dendrites, where
it is released and acts as a retrograde messenger. Despite
this work in nonhumans, it has been unclear what role
BDNF played in the greatly expanded, verbally mediated
episodic memory in humans.
The BDNF gene is 66.8 kilobases, has 9 exons, and pro-
duces at least 6 splice variants. All 5´ exons are spliced
out and only the final 3´ exon is translated into protein.
Translation produces a precursor protein, which is pack-
aged into secretory vesicles and eventually cleaved at
amino acid 128 to form the mature BDNF protein. The
BDNF gene was recently found to contain at least one
common polymorphism that changes amino acid
sequence. This is the val66met polymorphism at codon
66, which creates a valine to methionine substitution in
the preprotein. Other missense single nucleotide poly-
morphisms (SNPs) have been described, but appear to
be uncommon. Because val66met is only in the prepro-
tein, it has no effect on the structure or in vitro activity
of the mature BDNF protein.
The relevance of this polymorphism for humans was first
Copyright © 2005 LLS SAS. All rights reserved
The genetic determinants of human brain function have long been elusive, but are now begin-
ning to emerge. The conjunction of the sequencing of the human genome (ie, the discovery of all
genes) with the development of new neuroimaging techniques has produced an astonishing leap
forward in our ability to detect the effects of genes on neurobiological processes. This poster
focuses on a prototypical study of the gene for brain-derived neurotrophic factor (BDNF),
showing its role in human hippocampal function and memory.
