Dr. Huber made the original discovery of the mGluR Theory of Fragile X when she was a postdoctoral fellow in the lab of Dr. Mark Bear, with her first FRAXA grant in 2000. Dr. Huber has received $474,300 in grants from FRAXA Research Foundation since then, researching molecular mechanisms and developmental switches in Fragile X syndrome. She has worked with 4 FRAXA Postdoctoral Fellows (Elena Nosyreva, PhD in 2006; Jennifer Roseni, PhD in 2007; Tong Zang, PhD in 2010-2011; and Weirui Guo, PhD in 2012-2013) and has received supporting funds from The Meadows Foundation of/for Texas.
Developmental Study of FMRP Dependent Synapse Regulation in Fragile X Syndrome
Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of Fragile X syndrome. Little is known about the molecular mechanisms that cause overactive mGluR5 in Fragile X. mGluR5 is less associated with its intracellular scaffolding protein, Homer, in Fragile X syndrome mice (Fmr1 KO) which is linked with overactive mGluR5 and mGluR5 dysfunction in Fragile X. Drs. Guo and Huber tested their hypothesis that enhanced phosphorylation of Homer by a specific Homer kinase, CaMKII, occurs in the brains of Fmr1 KO mice and leads to enhanced mGluR5 function and Fragile X phenotypes. These experiments would determine if Homer kinases, such as CamKII, could be therapeutic targets for Fragile X syndrome.
Weirui Guo, PhD
2011: Evaluation of CamKII Dependent Regulation of mGluR5-Homer Scaffolds as a Potential Therapeutic for Fragile X Syndrome
Proper synapse maturation and elimination is crucial for the establishment of appropriate neural circuits that underlie sensory processing and cognition. Neuron of Fragile X patients as well as in the mouse model of Fragile X, Fmr1 KO mice, display more dendritic spines, the point of contact for excitatory synapses, as well as long and thin filopodia resembling immature spines. This suggests Fragile X mental retardation protein (FMRP) has a role in promoting synapse maturation and elimination. Altered regulation of these processes in Fragile X syndrome likely underlies many of the cognitive deficits associated with Fragile X syndrome.
There is considerable evidence that synaptic plasticity and structure are altered in Fmr1 KO mice, but the mechanisms by which this occurs are unknown. Previously we demonstrated that acute postsynaptic expression of FMRP in CA1 pyramidal neurons in slice cultures elicits synapse elimination providing a direct cell autonomous role for FMRP in synapse elimination (Pfeiffer et al., 2007). We have gained important mechanistic insight into FMRP induced synapse elimination. The activity-dependent transcription factor, myocyte enhancer factor 2 (MEF2) also causes synapse elimination in neurons. We find that FMRP is required for MEF2 to elicit synapse elimination. Importantly, FMRP functions downstream of MEF2 activation and active MEF2 is required for FMRP to eliminate synapses (Pfeiffer, Zang et al., Neuron, 2010).
Most recently, we have observed developmental differences in the effects of acute FMRP expression on synaptic function. The developmental difference will give us a hint of how the disease occurs and proceeds. We hypothesize that these differences are due to developmental regulation of candidate transcription factors. We anticipate that our results will gain a better understanding of how FMRP regulates synapse development, why synapse density, maturation and connectivity are altered in Fragile X syndrome and may lead to novel therapeutic strategies for the disease.
Our project had these aims:
Aim 1: Determine if there is a developmental switch in the effects of FMRP on dendritic spine structure and number.
Aim 2: Determine whether developmental regulation of MEF2 accounts for the switch of FMRP on synapse number.
Aim 3: Test MeCP2 as a transcription factor which regulates FMRP function in young neurons.
The team found that the developmental switch of postsynaptic FMRP on synaptic function is controlled by MEF2 transcriptional activity.
Tong Zang, PhD