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Fragile X, MHC Proteins Shape Synapses

Adapted from a story that originally appeared on the Alzheimer Research Forum.

19 April 2007. The ability of synapses to strengthen or weaken, form anew, or disappear entirely underlies the brain’s capacity to establish functional neuronal circuits during development and to learn and remember later on in life. Two new papers probe the roles of distinct proteins that regulate this process. Work on the Fragile X syndrome protein FMRP, and the immune receptor/neural regulator MHC Class I reveal new insights into how these proteins act within the complex ensemble of players that regulate synapse dynamics.

Neither protein has been tied to schizophrenia, but the development of proper circuitry (Weinberger, 1987; Murray and Lewis, 1987) and the function of mature synapses (for review, see Harrison and Weinberger, 2005; Owen et al., 2005) are certainly major foci of interest among schizophrenia researchers.

In a paper published online April 8 in Nature Neuroscience, Claudia Bagni from the Universita “Tor Vergata” in Rome, Italy, and colleagues from Scotland and England describe an additional target for FMRP, the messenger RNA for the postsynaptic density 95 (PSD-95) protein. In contrast to other mRNAs whose translation FMRP regulates, the new data shows that FMRP increases the stability of PSD-95 mRNA. Led by first authors Francesca Zalfa, Boris Eleuteri, and Kirsten Dickson, the researchers show that the stabilization is further enhanced by glutamate receptor activation. In mice lacking the FMRP protein, PSD-95 mRNA and protein levels are decreased in the hippocampus.

Although a large number of potential FMRP targets have been identified in recent years, only a few are known to play a role in regulating synapse structure and function, the authors write. The addition of PSD-95 to this short list supports the idea that FMRP is important for establishing proper synaptic structure, function, and plasticity. Moreover, the dysregulation of PSD-95 could be a factor in the cognitive impairment seen in Fragile X syndrome. There have been tentative links between PSD-95 and schizophrenia, including a finding of decreased expression in postmortem tissue (Clinton and Meador-Woodruff, 2004).

A second report, from Carla Shatz and colleagues at the Harvard Medical School in Boston, Massachusetts, and Stanford University in Palo Alto, California, shows how another set of proteins function from a postsynaptic location near PSD-95 to regulate plasticity in response to synaptic activity. MHC Class I (MHCI) proteins are a well-known player in the immune system, and several years ago Shatz showed their unexpected involvement in activity-dependent synaptic remodeling during development and in the adult brain (see SRF related news story).

In the new work, out April 9 in PNAS online, Alex Goddard, Daniel Butts, and Shatz first showed by immunostaining that MHCI is localized in postsynaptic areas of cultured hippocampal neurons, with a distribution that largely overlaps with that of PSD-95. Then, the scientists found several abnormalities in the synaptic structure and function of mice lacking MHCI. Cultured neurons or brain slices from knockout mice showed increased frequency of mini-EPSCs, suggesting that basal transmission was abnormal. The enhanced presynaptic activity was associated with a modest increase in the size of presynaptic boutons, and slightly elevated numbers of synaptic vesicles.

These functional and structural changes in knockout mice resembled the changes seen in neurons where synaptic activity is blocked using tetrodotoxin (TTX). When the researchers treated MCHI knockout neurons with TTX, the neurons showed no further changes in synaptic activity or structure, consistent with their having already adopted a TTX-treated synaptic phenotype. The researchers reasoned that down regulation of MHCI could be responsible for TTX-induced synaptic changes. Indeed, Shatz and colleagues first identified MHCI in the nervous system because its expression was reduced in the brain of TTX-treated cats (Corriveau et al., 1998). In the current work, they found that treating cultured neurons from wild-type mice treated with TTX resulted in the expected synaptic changes and lower expression of MHCI mRNA and protein.

“A major finding of this study is that MHCI is part of the molecular machinery regulating synaptic morphology and function under basal conditions and following action potential blockade,” the authors write. They note that postsynaptic MHCI also appears to act across the synapse to change presynaptic structures in response to activity.—Pat McCaffrey.

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