Rett syndrome

Rett syndrome (RS) is a devastating neurodevelopmental disorder characterized by loss of language skills, stereotyped behaviors, autistic-like features, cognitive deficits, seizures, and breathing abnormalities. The majority of RS cases are caused by mutations in the methyl CpG binding protein, MeCP2. Knockout (KO) of the mouse Mecp2 gene recapitulates many RS phenotypes and re-expression of MeCP2 in adult animals corrects numerous phenotypic deficits. This would suggest that RS does not need to exist as a lifelong condition, but rather is a disorder that can be reversed with the proper treatment strategy. Unfortunately, very few genes have been characterized whose expression changes dramatically with loss of Mecp2, and even fewer have been identified that might be explored therapeutically.

Using a combination of bioinformatics and preclinical basic science research, we have established that metabotropic glutamate receptor 7 (mGlu7) may be one such target, and we have recently expanded these studies with the goal of understanding the roles of all the metabotropic glutamate receptors in RS. mGlu7 acts as an auto- and heteroceptor to modulate the release of both glutamate and GABA from presynaptic neuron terminals and is expressed widely in brain areas that are thought to contribute to major RS symptoms. Our preliminary data indicate that the gene encoding mGlu7 is positively regulated by MeCP2 both in rodents and in humans, and we have found that mGlu7 mRNA and protein levels are significantly decreased in multiple brain areas in Mecp2-/y KO mice. As one function of mGlu7 activation is to decrease glutamate release from presynaptic terminals, we hypothesize that decreased mGlu7 levels in Mecp2 KO mice results in hyperglutamatergic tone, disrupting neurotransmission. In the hippocampus of late-symptomatic Mecp2 mutant or KO mice, excitatory Schaffer collateral-CA1 (SC-CA1) synapses exhibit decreased paired-pulse facilitation, suggestive of a presynaptic deficit resulting in enhanced excitation, as well as impaired long term potentiation (LTP). In support of this, we can restore paired-pulse ratios and normalize LTP with two distinct positive allosteric modulators (PAMs) of mGlu7. The two PAMs we have used to validate our hypothesis potentiate all of the group III mGlus, mGlu4, mGlu6, mGlu7, and mGlu8; however, by coupling our pharmacological tools with a synapse that only expresses mGlu7, we are confident that we are restoring these hippocampal synaptic plasticity deficits via an mGlu7-mediated mechanism. Additionally, to circumvent the selectivity limitations of our current PAMs, we have also employed an mGlu7 negative allosteric modulator (NAM) to verify mGlu7-dependent effects. We plan to extend our findings to other synapses and in vivo assays thought to be important for the phenotypic domains of RS. In parallel, we are pursuing a chemical optimization campaign to develop compounds with improved selectivity and pharmacokinetic profiles to further validate mGlu7 as a therapeutic candidate for RS.

In addition to our work with mGlu7, we have also found a role for mGlu5 in the potential treatment of RS. In Rett patients and mice, both protein synthesis dependent and independent forms of synaptic plasticity are attenuated depending on the age and brain region examined; thus, positive allosteric modulators of mGlu5 are believed to hold therapeutic potential via their ability to potentiate glutamatergic signaling and enhance multiple forms of long-term synaptic plasticity. Unfortunately, mGlu5 drug development and pre-clinical use have been hampered by target-mediated adverse effects that present with positive modulation of this pathway. The most common of these adverse events are convulsive in nature, and since Rett patients and model mice are already highly susceptible to seizures, this represents a particularly relevant challenge for their use as Rett therapeutics. Excitingly, we have recently generated a novel understanding of how mGlu5 PAM properties contribute to the induction of seizures and have now generated compounds that potentiate mGlu5-mediated glutamatergic signaling without inducing behavioral convulsions, representing an important therapeutic advancement for mGlu5 drug development. In RS model mice, we have found that one of our novel mGlu5 PAMs significantly reverses advanced stage Rett phenotypes, such as hind limb clasping and gait abnormalities. Importantly, this is accomplished in both chronic and acute dosing paradigms without inducing any quantifiable behavioral convulsions, providing optimism that mGlu5 PAMs are viable therapeutic targets for Rett syndrome.

If you are interested in learning more about Rett syndrome studies ongoing at the VCNDD, please contact Colleen Niswender ( for further discussion.

Fragile X

Parents hope to pass along many things to their children, but Fragile X syndrome (FXS) is never included on that list. This genetic condition is the most commonly inherited intellectual disability, affecting 1 in 3600 males and 1 in 4000 to 6000 females each year. Fragile X syndrome is also attributed as the most common cause of autism. FXS patients display many autism-associated behaviors such as hypersensitivity to environmental stimuli, repetitive behavior, and social anxiety. The severity of these symptoms ranges from learning disabilities to severe cognitive and intellectual disabilities. Symptoms can also include characteristic physical features, delays in the development of speech and language, and epileptic seizures.


Until recently, intellectual disability, including FXS, has largely been considered an incurable condition, and currently available treatments are designed to manage individual symptoms, such as anxiety, attention span, or seizures, rather than to improve cognitive deficits or correct the disease process. Each of the medicines used for managing these individual symptoms has its own side effects and none fundamentally alters the course of development of children suffering from this devastating disorder. While special education, speech and language therapy, occupational therapy, and behavioral therapy are necessary and can help to improve the quality of life for FXS patients, new pharmaceutical treatments that can correct the underlying disease process and improve multiple symptoms are desperately needed.


In the 1990s, a key breakthrough in FXS research occurred-the isolation and characterization of the human gene linked to the disease. Discovery of this mutation led to greatly enhanced understanding of the disease. Researchers postulated that overactive or aberrant neurological signaling through a certain protein found in the brain might be linked to FXS. Additional research identified a specific drug target for "tuning down" the signaling through this particular protein, and results were dramatic. These studies suggest that a medicine that acts at this specific target in FXS patients could reverse the myriad of pathological changes that give rise to this disorder. Not only does evidence suggest that such an approach may offer improvement for many behavioral symptoms related to FXS, but it also offers the potential to treat the cognitive deficits as well.