August 25, 2003
BDNF Gene Variations Affect Ability To Make, Recall Visual Memories

Differences in the brain derived neurotrophic factor (BDNF) gene cause differences in memory formation and recall capabilities.

In the new research, reported in the Journal of Neuroscience, Daniel R. Weinberger and his colleagues at the National Institute of Mental Health in Bethesda, Maryland, studied 28 people who carried genes that encoded either the “Val” form or the “Met” form of the BDNF protein.

People with the "Val" form of BDNF are better at recalling visual memories.

The researchers noticed significant differences in brain activity between the two groups during both the encoding and retrieval phases of the task. Those with the “Val” form of the gene were better at remembering pictures than were those with the “Met” form, and they also had greater brain activity during the encoding and retrieval phases of memory.

There are still other factors at work besides BDNF gene variations.

Remarkably, the interaction between the BDNF val66met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.

So you might be thinking that it is better to have two copies of the "Met" form of BDNF. Well, not so fast. It depends on what kind of memory you want to be better at forming and recalling. Earlier work by the same group of scientists showed that the "Val" variant is better for recalling episodic memory.

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.

These scientists are tracing the differences in memory recall all the way down to the molecular level.

Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF and its val/met polymorphism in human memory and hippocampal function and suggest val/met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF.

It is quite possible that there exist variations of other genes which complement either the "Val" or "Met" variations so as to allow superior memory formation and recall for both episodic and visual memories.

Share |      Randall Parker, 2003 August 25 12:07 PM  Brain Genetics

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