BDNF, fragile X syndrome, and memory

Researchers restored the capacity to retain new memories in fragile X syndrome mice by infusing BDNF to the hippocampus region.
This study shows that an infusion of BDNF (brain derived neurotrophic factor) can restore the ability of mice with fragile X syndrome to retain new memories.

Long term potentiation (LTP) of hippocampal neurons is impaired in fragile X syndrome. LTP involves the ability of those neurons to retain a heightened voltage potential after stimulation. This is part of the process by which short term memories are consolidated and stored as long term memories. The same impairment exists in Huntington's Disease (for the HD study, see HDL: Toward a treatment of cognitive/behavioral symptoms with BDNF).

Interest in increasing BDNF as a treatment for neurological disease continues to grow. This increases the likelihood that a BDNF treatment will be developed soon. Gene therapy to boost BDNF is a possibility and so is drug treatment. Ampakines are being investigated (see HDL: Ampakines). Further, a small molecule to mimic BDNF has been developed and is being tested.

In the meantime, many of those at risk and those who are symptomatic are pursuing a proactive strategy to boost BDNF through exercise. Another known ways are listening to music and the use of SSRI antidepressants.

Marsha L. Miller, Ph.D.
Julie Lauterborn, Ph.D.
Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome.
Julie Lauterborn, Christopher Rex, Eniko Kramar, Lulu Y. Chen, Vijay Pandyarajan, Gary Lynch, and Christine Gall
The abstract

Mice lacking expression of the fragile X mental retardation 1 (Fmr1) gene have deficits in types of learning that are dependent on the hippocampus. Here, we report that long-term potentiation (LTP) elicited by threshold levels of theta burst afferent stimulation (TBS) is severely impaired in hippocampal field CA1 of young adult Fmr1 knock-out mice. The deficit was not associated with changes in postsynaptic responses to TBS, NMDA receptor activation, or levels of punctate glutamic acid decarboxylase-65/67 immunoreactivity. TBS-induced actin polymerization within dendritic spines was also normal. The LTP impairment was evident within 5 min of induction and, thus, may not be secondary to defects in activity-initiated protein synthesis. Protein levels for both brain-derived neurotrophic factor (BDNF), a neurotrophin that activates pathways involved in spine cytoskeletal reorganization, and its TrkB receptor were comparable between genotypes. BDNF infusion had no effect on baseline transmission or on postsynaptic responses to theta burst stimulation, but nonetheless fully restored LTP in slices from fragile X mice. These results indicate that the fragile X mutation produces a highly selective impairment to LTP, possibly at a step downstream of actin filament assembly, and suggest a means for overcoming this deficit. The possibility of a pharmacological therapy based on these results is discussed.

Press Release: Study identifies memory-forming genetic deficit in fragile X syndrome and possible treatment

Irvine, Calif., October 5, 2007

University of California, Irvine scientists have discovered how to reverse the learning and memory problems inherent in the most common form of mental impairment.

Neurobiologist Julie Lauterborn and her colleagues identified how a mutated gene linked to fragile X syndrome blocks brain cells from locking new memories into lasting ones. The gene – called fragile X mental retardation 1 (Fmr1) – is turned off in people with fragile X syndrome. This genetic mutation disrupts cellular processes that are needed for memory formation.

The researchers found that by adding brain-derived neurotrophic factor (BNDF) proteins to the hippocampus region of fragile X syndrome test mice, memory-forming capacities of the brain cells were completely restored. The findings, which are reported in the Journal of Neuroscience, suggest the possibility of fragile X syndrome therapies that allow for increased learning and memory.

“While this discovery doesn’t identify a cure for fragile X syndrome, it provides the scientific foundation for methods to treat its learning and memory deficits,” Lauterborn said.

In their study, the researchers reported how the loss of a functional Fmr1 gene impaired a process called long-term potentiation (LTP) in the hippocampus region of the brain where memories are created and stored. LTP describes a chemical process that literally strengthens a synapse. Synapses are the connection points between neurons where single cells are functionally coupled to other cells.

Since memories are believed to be formed and stored within synapses, LTP is widely considered one of the major mechanisms by which the brain learns and maintains memories. This LTP impairment limits the ability of cells in the hippocampus to modify the strength of synapses, thus blocking long-term memory formation.

Earlier this year, a UC Irvine research team led by neurobiologists Gary Lynch and Christine Gall showed the first images of LTP forming memories in brain cells and how neurodegenerative diseases can obstruct the LTP process. These studies were reported in the Journal of Neuroscience.

Fragile X syndrome is the most common inherited cause of mental impairment, according to the National Fragile X Foundation. The syndrome occurs in approximately one in 3,600 males and one in 4,000 to 6,000 females. It is caused by a change or mutation in a gene on the X chromosome.

The majority of males with fragile X syndrome have a significant intellectual disability, ranging from learning disabilities to severe mental retardation, and autism. Females often have milder intellectual disabilities. There is currently no treatment that improves cognitive function in this syndrome. For more information, see: www.fragilex.org.

Lynch, Gall, Christopher Rex, Eniko Kramar, Lulu Y. Chen and Vijay Pandyarajan of UC Irvine worked on the study, which received support from the National Institutes of Health, the UC Industry-University Cooperative Research Program and a UC Discovery grant.

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The Journal of Neuroscience 2007 Oct 3;27(40):10685-94.