Suzanne Zukin, PhD, Principal Investigator
Kirsty Sawicka, PhD, Postdoctoral Fellow (2011)
Sho Fujisawa, PhD, FRAXA Postdoctoral Fellow
Yukihiro Takayasu, PhD, FRAXA Postdoctoral Fellow (2006)

FRAXA Awards:

by Kirsty Sawicka, 5/1/2011

Neurons form vast interconnected networks that are essential for brain function. They are connected via synapses that allow signals to pass from one neuron to the next. Synaptic plasticity is the modulation of connections between neurons in response to synaptic transmission, including both decreases and increases in synaptic strength, and is fundamental to learning and memory.

Activation of metabotropic glutamate receptors (mGluRs) triggers modifications in synaptic strength and structure by rapid stimulation of protein synthesis at synaptic sites. It is well established that mGluR signalling is dysregulated in Fragile X and therapeutic interventions to correct this aberrant signalling have shown promising results. Research in our laboratory focuses on signalling pathways downstream of mGluRs that are causally related to impaired synaptic plasticity and cognition. We have shown that mTOR, a critical regulator of protein synthesis downstream of mGluRs, is overactivated in Fragile X mice and may account for aberrant synaptic plasticity. We further showed that PIKE (PI3K enhancer), an identified target of FMRP and key player that links mGluRs to mTOR, is elevated in Fragile X mice.

The goal of the proposed study is to establish whether PIKE represents a potential therapeutic target for the treatment of Fragile X. We hope that by restoring PIKE expression to normal levels in Fragile X mice, we will be able to correct aberrant signalling, protein synthesis and synaptic plasticity. We will use two complementary genetic strategies to manipulate PIKE expression, acute knockdown of PIKE by injection of lentiviral shRNA directly into the brain of live animals and transgenic mice in which the PIKE gene is knocked out. If successful, these experiments will establish PIKE as a novel therapeutic target for the treatment of Fragile X syndrome and open doors for the development of new drug molecules.

by Michael Tranfaglia, FRAXA, 4/2/2007

The long-term goal of this research is to elucidate the molecular mechanisms underlying regulated AMPA recptor trafficking in dendrites under physiological and pathological (fragile X) conditions. Our hypothesis is that cognitive impairments in Fragile X result from dysregulation of messenger RNA localization and local protein synthesis. We will use a combination of molecular, biochemical and imaging techniques to examine activity-dependent and developmental regulation of mGluR-dependent trafficking of AMPA receptor mRNAs in dendrites and targeting to synaptic sites in neurons from wild-type and Fmr1 KO mice. An important goal is to identify possible alterations in AMPAR mRNA trafficking in the fragile X mouse. In addition, we will identify signaling pathways involved in regulation of dendritic targeting of AMPAR mRNAs and local protein synthesis and examine their possible dysregulation in KO mice. A focus will be on the PI3-kinase, CREB and mTOR signaling cascades known to be downstream of group I mGluR activation and important to local protein synthesis. Understanding the mechanisms underlying abnrmalities of mGluR-dependent synaptic plasticity could help in the development of novel therapeutic strategies to ameliorate cognitive deficits in Fragile X Syndrome.

by Suzanne Zukin, 3/6/2006

Regulated mRNA trafficking and local protein synthesis play central roles in synaptic remodeling and plasticity. By spatially restricting gene expression within microdomains, local protein synthesis endows neurons with the capacity to autonomously regulate their structure and function.

We recently found that AMPAR mRNAs are targeted to synapses and that mGluR activation promotes targeting of AMPAR mRNAs to synaptic sites. The goal of this project is to determine if dysregulation of mRNA localization and local protein synthesis impairs synaptic transmission, using the Fragile X mouse model. We will use a combination of molecular biological and live-cell imaging techniques to examine precisely how stimulating mGluRs affects AMPA receptor mRNA targeting to synaptic sites and local synthesis of AMPA receptor protein in dendrites.

Understanding the mechanisms underlying dysregulation of mGluR-dependent synaptic plasticity could help in the development of novel therapeutic strategies to ameliorate cognitive deficits in Fragile X Syndrome.