Joel Richter, PhD
Principal Investigator
Natalie Farny, PhD
Postdoctoral Fellow
Univ. of Massachusetts Medical School

FRAXA Awards:
  $45,000 in 2010
  $40,000 in 2009
  $40,000 in 2008

The connections in our brains are constantly changing. As we interact with our environment and with each other, the connections between our neurons are remodeled so that we can retain these interactions as learning and memory. At a molecular level, the brain accomplishes this remodeling in part by making new proteins (a process known as protein synthesis) at the specific sites where our neurons interact with each other (known as synapses). The development of new synaptic connections and the pruning away of old ones through the process of protein synthesis is the molecular basis for learning, memory, and behavior. The process of synaptic remodeling, of strengthening and weakening of connections between neurons, is known as synaptic plasticity. Defects in synaptic plasticity are seen in many neurological disorders, including Fragile X Syndrome, which result in problems with learning and behavior.

There are many proteins required for the regulation of protein synthesis in synapses. One such protein is known as FMRP, the product of the Fragile X mental retardation gene. In individuals suffering from Fragile X Syndrome, FMRP is not present to regulate protein synthesis in neurons, and synaptic plasticity is negatively affected.

In our lab at the University of Massachusetts Medical School, we study another protein that is important for regulating protein synthesis in synapses, known as CPEB. We noted that CPEB and FMRP seem to have opposite effects on protein synthesis: FMRP is generally thought to inhibit protein synthesis, and CPEB is thought to activate protein synthesis. These two proteins may thus be important for maintaining a balance of protein synthesis at the synapse; in the absence of one of these proteins, the activity of the other becomes excessive, and defects of synaptic plasticity will result. We hypothesize that when FMRP is absent, reducing or eliminating the activity of CPEB could correct this imbalance of protein synthesis and restore normal synaptic plasticity.

To test our hypothesis, we bred mice lacking FMRP with mice lacking CPEB, to create mice that are missing both genes (“double knockout” mice). In an exciting series of experiments, we have seen that certain defects in synaptic plasticity that are characteristic of FMRP null mice are corrected in the double knockout mice. Currently, we are working to examine whether other behavioral and molecular phenotypes of Fragile X mice are corrected in our double knockout mice.

Our preliminary results suggest that decreasing the activity of CPEB in the brain could be a useful therapeutic strategy for treating Fragile X Syndrome. We are currently designing a screen to identify drug compounds that inhibit the activity of CPEB. Our hypothesis is that inhibiting CPEB activity in the brain could restore the balance of protein synthesis in the brains of both Fragile X mice and humans, similar to the corrective effects we see in double knockout mice. We plan to screen hundreds of thousands of compounds to find a drug that inhibits CPEB, which could one day be used as a new treatment for the Fragile X Syndrome.

by Joel Richter, 6/2008

Synaptic plasticity, the ability of synapses to undergo biochemical and morphological changes in response to experience, is thought to underlie essential brain functions such as learning and memory. This plasticity requires changes in gene expression at multiple levels, including translational control. One factor that appears to modulate translation is FMRP, the product of the Fragile-X mental retardation gene. While the syndrome caused by malfunction of the Fragile X gene is a complex disease with several symptoms, the neural pathology has been linked to defects in certain forms of synaptic plasticity. Thus, it appears that FMRP-regulated translation, perhaps in the synapto-dendritic compartment, is necessary for normal synapse and neuronal function. However, the precise function of FMRP in translation is unclear; while some evidence suggests that it represses translation, results from other studies are not necessarily consistent with this model.

CPEB is another protein that controls translation in neurons; it binds specific mRNAs and modulates RNA expression by regulating poly(A) tail length. CPEB is detected throughout the brain and is present at synapses as well as in the cell body. CPEB is bifunctional; it represses translation by keeping poly(A) tails short but in response to certain signaling events such as those elicited by synaptic stimulation, it induces poly(A) tail lengthening and translational activation. Presumably through its translational control and/or dendritic RNA targeting function, CPEB also modulates synaptic plasticity.

We have found that CPEB and FMRP interact both in vitro and in vivo. Based on this and other observations, we hypothesize that FMRP and CPEB may act in a reciprocal manner to control translation of a common set of mRNAs. These two proteins may thus be important for maintaining synaptic protein homeostasis through mRNA translational control; when the synthesis of one or more of these proteins becomes imbalanced, diseases such as the Fragile-X syndrome result. We propose to combine genetic and biochemical approaches to test the hypothesis that FMRP and CPEB act in concert to modulate the levels of specific proteins in neurons. We are hopeful that our experiments will provide new therapeutic approaches to treat the Fragile X syndrome.