Novel target identified for fragile X-linked autism

Oct 1 2012

By Andrew Czyzewski, medwireNews Reporter

Researchers have elucidated a novel mechanism through which fragile X syndrome may contribute to behavioural symptoms of autism and identified a potential therapeutic target.

Using a mouse model, they found that knocking-out the gene encoding fragile X mental retardation protein caused the disruption of a special type of synaptic transmission that is dependent on an endocannabinoid factor.

Crucially, pharmacologic enhancement of this endocannabinoid restored some of the behavioral abnormalities of the knock-out mice, including impaired performance in a maze test.

"What we hope is to one day increase the ability of people with fragile X syndrome to socialize and engage in normal cognitive functions," said study co-author Daniele Piomelli (University of California, Irvine, USA) in a press statement.

Fragile X syndrome, the most frequently known genetic cause of autism, is characterized by a series of physical, cognitive, and emotional symptoms that include social deficits and a diminished ability to learn. Fragile X syndrome is due to the mutation of a single gene, called FMR1, which encodes the fragile X mental retardation protein.

In the current study, Piomelli and colleagues performed a raft of immunochemical assays on brain tissue taken from double knockout fmr1 ^{- / -} mice and wild-type mice.

They found that, in the mutant mice, the synapses of the ventral striatum and prefrontal cortex showed a disruption in a type of glutamate-dependent long-term depression (LTD).

Such LTD is a result of a reduction in the excitability of neuronal synapses, lasting hours or longer, and is a vital aspect of synaptic plasticity.

They subsequently found that this LTD is initiated by the endocannabinoid neurotransmitter, 2-arachidonoyl-sn-glycerol (2-AG), which acts in a retrograde fashion - by diffusing from the postsynaptic cleft to the presynaptic cleft -the opposite direction to classic neurotransmission.

However, in fmr1 ^{- / -} mutant mice, 2-AG appears to be degraded enzymatically, particularly by monoacylglycerol lipase, thereby disrupting LTD.

Notably, when the researchers treated mice with a pharmacologic inhibitor of MGL they saw dramatic behavioral improvements in maze tests measuring anxiety and open-space acceptance.

"The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy," Piomelli et al comment in Nature Communications.

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