|PIKE as a central regulator of synaptic dysfunction in Fragile X Syndrome
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.