AMPAkines and BDNF in Fragile X: UCI Researchers Restore Memory Process in Fragile X

With funding from FRAXA Research Foundation from 2003-2008, Dr. Julie Lauterborn at the University of California has done several studies on dentritic spines and finding treatment targets for memory retention in Fragile X mice. Results published.

$104,498 Grant
Julie Lauterborn, PhD
Principal Investigator
University of California at Irvine
FRAXA Research Grants
$64,498 (2008)
$40,000 (2003)

UC Irvine Press Release , 10/5/2007

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.

Therapeutic Strategies for Cognitive Impairment in Fragile X: AMPAkines

by Julie Lauterborn, 6/1/2003

This study complements Dr. Berry-Kravis’s human trial of the Ampakine drug CX516. Dr. Lauterborn aims to understand the actions of newer Ampakine compounds which are not yet tested for human use but which are more potent than CX516.

Fragile X (FX) syndrome and other forms of mental retardation are characterized by abnormalities in the dendritic spines of cortical pyramidal cells: spines are longer and more numerous, features suggesting that they are relatively immature.

Mice with transgenic mutation of the Fmr1 gene encoding the Fragile X Mental Retardation Protein (FMRP) have similar alterations in spine morphology, and other abnormalities in cortical fields including reduced levels of some ionotropic (i.e. AMPA) glutamate receptor subunits, and hyper-responsive function of the group 1 metabotropic glutamate receptor 5 (mGluR5). Additionally, FX mice have deficient Long Term Potentiation (LTP), the presumable cellular substrate of memory, and learning deficits. Thus, this mutant is useful for testing hypotheses as to the consequences of lost FMRP expression on spine shape/density and synaptic plasticity, and for testing manipulations intended to counteract these consequences.

Studies show that AMPA treatment leads to a rounding and normalization of spine morphology whereas treatment with brain derived neurotrophic factor (BDNF) leads to a reduction in spine number and a shortening of surviving spines. Recent studies by Dr. Lauterborn demonstrate that BDNF treatment restores hippocampal LTP in FX mice. These data suggest that interventions that target AMPA-class receptors and augment neurotrophin availability, such as ampakine treatment, could be of tremendous value for correcting abnormalities in dendritic spines and synaptic function associated with mental retardation. Moreover, other work by Dr. Lauterborn demonstrates that mGluR5 antagonism in combination with ampakine treatment elicits even greater elevations in BDNF expression than does the ampakine alone, suggesting that a combined therapeutic approach may be more beneficial for enhancing neurotrophism.

These studies are designed to test the hypothesis that in the Fmr1 knockout (KO) mouse treatment with ampakines, which positively modulate AMPA- receptors (AMPARs) and increase BDNF expression, will induce maturation-like changes in the morphologies of cortical dendritic spines. Ampakines will be evaluated for effects on BDNF protein levels and spine abnormalities, either alone or in combination with an mGluR5 antagonist. They will test whether co-treatment with ampakines and mGluR5 antagonists will induce greater increases in BDNF protein content than with ampakines alone; studies will evaluate with two ampakines with different half-lives. They will also test whether ampakine/mGluR5 antagonist co-treatment will induce maturation-like changes in dendritic spines in adult Fmr1-KOs, and that the effects of combined therapy will be greater than either drug alone. Studies will test if treatment influences spine shape and number to normalize these features in a newly created FMR1-KO hybrid that expresses yellow fluorescent protein in individual cortical neurons with labeling of dendritic spines.

Effects of Positive AMPA Receptor Modulation in the Fragile X Knockout Mouse

by Julie Lauterborn, 6/2003

Studies in Fragile X mice reveal abnormalities in the shape and number of dendritic spines (where neurons receive input from other neurons), similar to the abnormalities seen in brain cells of humans with Fragile X. In addition, in the Fragile X mouse there is less glutamate receptor protein in the forebrain, suggesting that cognitive deficits in this syndrome may arise from impaired maturation of glutamate spine synapses.

Stimulation of AMPA-class glutamate receptors leads to a normalization of spine shape and stimulates brain neurons to synthesize increased levels of Brain-Derived Neurotrophic Factor (BDNF). BDNF is known to reduce spine number and length, as well as to increase AMPA receptor protein levels. These findings suggest that in Fragile X (and in the mouse model), increases in both AMPA receptor and BDNF signaling may effect changes in synapses that should ameliorate deficits in neurotransmission.

Recently we demonstrated that Ampakines, which increase AMPA receptor function, also increase BDNF expression in normal rodents. The data suggest that Ampakines could be useful therapeutics for dendritic spine abnormalities and cognitive deficits associated with Fragile X. We will test the hypotheses that (1) the regulation of AMPA receptor expression within the cell membrane is similar in Fragile X knockout and wildtype mice and (2) Ampakine facilitation of AMPA receptor function can be used to sustain increases in neuronal BDNF protein content in Fragile X knockout neurons.

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