Fragile X mice have shortage of synaptic proteins
The brains of young mice with fragile X syndrome show a dearth of two proteins that are important at the synapse, the junction between neurons, researchers reported Tuesday at the Society for Neuroscience annual meeting in San Diego.
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Broken bridges: Fragile X mice make fewer autism-related proteins at the junctions between neurons.
The brains of young mice with fragile X syndrome show a dearth of two proteins that are important at the synapse, the junction between neurons, researchers reported Tuesday at the Society for Neuroscience annual meeting in San Diego.
Fragile X syndrome is a single-gene disorder that causes mental retardation and, often, autism. Jason Dictenberg‘s team at Hunter College in New York showed that after being stimulated, neurons in fragile X mutants do not make a protein called postsynaptic density-95, or PSD-95, which is important for organizing other proteins at the synapse. The animals also make low levels of neuroligin-1 (NLGN1), a protein that interacts with PSD-95 and helps form excitatory synapses.
PSD-95 and the neuroligin family of proteins have been linked to autism and related disorders, suggesting that synaptic abnormalities underlie the overlap of symptoms, the researchers say.
“In the broad spectrum of autism, in all of these disorders, you have trouble with the synapse,” says Valerie Drouet, a postdoctoral fellow in Dictenberg’s lab.
Fragile X syndrome is caused by the loss of the fragile X mental retardation protein, or FMRP. Scientists are just beginning to understand what the protein does, but one of its roles is to bind with RNA in the cell nucleus. Once linked, FMRP represses translation of the RNA into protein, setting the RNA free only after it shuttles it down neuronal branches to the synapse.
“This mechanism is really important for maturation and synaptic plasticity. So FMRP is a key molecule at the synapse,” Drouet says.
One of FMRP’s known RNA targets is PSD-95. Once at the synapse, PSD-95 interacts with NLGN1. The researchers measured levels of each protein in dendrites, or neuronal branches, from the hippocampus, a region important for learning and memory, in mice younger than 2 weeks.
Neurons in control mice show a large increase in PSD-95 and NLGN1 after being chemically stimulated. In contrast, “this very important increase is completely lost in the knockout mice,” Drouet says.
Because NLGN1 helps transmit excitatory electrical signals, the researchers also measured the number of excitatory and inhibitory synapses in the mutant cells. As expected, the mutants have fewer excitatory and more inhibitory synapses than do controls. This imbalance could be behind the seizures and sensory sensitivity seen in some people with fragile X syndrome, the researchers say.
For more reports from the 2010 Society for Neuroscience annual meeting, please click here.
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