PIKE as a Central Regulator of Synaptic Dysfunction in Fragile X Syndrome

With $255,000 in funding from FRAXA Research Foundation, Dr. Suzanne Zukin from Albert Einstein College of Medicine studied signalling pathways in Fragile X syndrome.

Results:Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome (2015)
$255,000 Grant
Suzanne Zukin, PhD
Principal Investigator
Albert Einstein College of Medicine
FRAXA Research Grants
$90,000 over 2011-2012
$165,000 over 2006-2008

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, and is fundamental to learning and memory.

Research in our laboratory focusd on signalling pathways that are related to impaired synaptic plasticity and cognition. We have shown that mTOR, a critical regulator of protein synthesis, 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 this study was to establish whether PIKE is a potential therapeutic target for the treatment of Fragile X. We hoped 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 used two complementary genetic strategies to manipulate PIKE expression:

  1. acute knockdown of PIKE by injection of lentiviral shRNA directly into the brain of live animals and
  2. creating transgenic mice in which the PIKE gene is knocked out.

Kirsty Sawicka, PhD
Postdoctoral Fellow

Sho Fujisawa, PhD
FRAXA Postdoctoral Fellow

Yukihiro Takayasu, PhD
FRAXA Postdoctoral Fellow (2006)

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