Human gene affects memory
Jan. 24, 2003
Human gene affects memory NIH scientists have shown that a common gene
variant influences memory for events in humans by altering a growth factor
in the brain's memory hub. On average, people with a particular version of
the gene that codes for brain derived neurotrophic factor (BDNF) performed
worse on tests of episodic memory tasks like recalling what happened
yesterday. They also showed differences in activation of the hippocampus, a
brain area known to mediate memory, and signs of decreased neuronal health
and interconnections.
These effects are likely traceable to limited movement and secretion of
BDNF within cells, according to the study, which reveals how a gene affects
the normal range of human memory, and confirms that BDNF affects human
hippocampal function much as it does animals'.
Michael Egan, M.D., Daniel Weinberger, M.D., National Institute of Mental
Health (NIMH), Bai Lu, Ph.D., National Institute of Child Health and Human
Development (NICHD) and colleagues, report on their discovery in the January
24 issue of Cell.
Long known to be critical for the growth and survival of neurons, BDNF
has also recently been shown to play a key role in memory and hippocampal
function in animals. To find out if it works similarly in humans, the
researchers explored the consequences of a tiny variance in the human BDNF
gene, where its molecular makeup differs slightly across individuals. People
inherit two copies of the BDNF gene -- one from each parent in either of
two versions. Slightly more than a third inherit at least one copy of a
version nicknamed "met," which the researchers have now linked to poorer
memory.
It's called "met" because its chemical sequence contains the amino acid
methionine in a location where the more common version, "val," contains
valine.
"We are finding that this one amino acid substitution exerts a
substantial influence on human memory, presumably because of its effects on
the biology of the hippocampus," said Weinberger.
Despite its negative effect on memory, the "met" version's survival in
the human genome suggests that it "may confer some compensatory advantage in
other biological processes," note the researchers. Although they found that
it does not confer increased susceptibility to schizophrenia, they suggest
that the "met" variant might contribute to risk for or increase functional
impairment in -- other disorders involving hippocampal dysfunction, such as
Alzheimer's disease or mood disorders.
Drawing on participants in the NIMH intramural sibling study of
schizophrenia, Egan and colleagues first assessed their hippocampal function
and related it to their BDNF gene types.
Among 641 normal controls, schizophrenia patients, and their unaffected
siblings, those who had inherited two copies of the "met" variant scored
significantly lower than their matched peers on tests of verbal episodic
(event) memory. Most notably, normal controls with two copies of "met"
scored 40 percent on delayed recall, compared to 70 percent for those with
two copies of "val." BDNF gene type had no significant effect on tests of
other types of memory, such as semantic or working memory.
The researchers then measured brain activity in two separate groups of
healthy subjects while they were performing a working memory task that
normally turns off hippocampus activity.
Functional magnetic resonance imaging (fMRI) scans revealed that those
with one copy of "met" showed a pattern of activation along the sides of the
hippocampus, in contrast to lack of activation among those with two copies
of "val."
Next, an MRI scanner was used to measure levels of a marker inside
neurons indicating the cell's health and abundance of synapses -- tiny
junctions through which neurons communicate with each other. Again, subjects
with one copy of "met" had lower levels of the marker, N-acetyl-aspartate
(NAA), than matched individuals with two copies of "val." Analysis showed
that NAA levels dropped as the number of inherited "met" variants increased,
suggesting a possible "dose effect."
Unlike other growth factors, hippocampal BDNF is secreted, in part, in
response to neuronal activity, making it a likely candidate for a key role
in synaptic plasticity, learning and memory. To explore possible mechanisms
underlying the observed "met"- related memory effect, the researchers
examined the distribution, processing and secretion of the BDNF proteins
expressed by the two different gene variants within hippocampal cells. When
they tagged the gene variants with green fluorescent protein and introduced
them into cultured neurons, they discovered that "val" BDNF spreads
throughout the cell and into the branch-like dendrites that form synapses,
while "met" BDNF mostly clumps inside the cell body without being
transported to the synapses. To regulate memory function, BDNF must be
secreted near the synapses.
"We were surprised to see that 'met' BDNF secretion can't be properly
regulated by neural activity," said Lu.
The observed memory decrements are likely traceable to the failure of
"met" BDNF to reach the synapses, as well as its inability to secrete in
response to neuronal activity, say the researchers.
"Our study provides direct in vivo data that the molecular mechanisms
related to activity dependent BDNF secretion and signaling, such as synaptic
plasticity, may underlie humans' greatly expanded verbally-mediated memory
system, just as it does for more rudimentary forms of memory in animals,"
said Egan.
In following-up their leads, the researchers are searching for a possible
BDNF connection with the memory problems and hippocampal changes of
Alzheimer's disease, depression and normal aging.
Also participating in the study were: Drs. Joseph Callicott, Terry
Goldberg, Bhaskar Kolachana, Alessandro Bertolino, NIMH; Drs. Masami Kojima,
Eugene Zaitsev, NICHD; Dr. David Goldman, National Institute on Alcohol
Abuse and Alcoholism (NIAAA); Drs. Bert Gold, Michael Dean, National Cancer
Institute (NCI).
NIMH, NICHD, NIAAA and NCI are part of the National Institutes of Health
(NIH), the Federal Government's primary agency for biomedical and behavioral
research. NIH is a component of the U.S. Department of Health and Human
Services.
National Institues of Health
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