25 August 2006. Molecules of the immune system may look a bit out of place on neurons, but they are increasingly revealing themselves as important players in the brain. Six years ago, Carla Shatz and colleagues from Harvard Medical School found that class I major histocompatibility complex proteins (MHCI), which function as antigen-presenting receptors in the immune system, regulate synaptic plasticity in the visual cortex (see ARF related news story). Now, the same group has found that an MHCI binding partner, the protein PirB, likewise restricts synaptic plasticity in the same system.
The results suggest that PirB, along with MHCI, could have a role in generally suppressing plasticity, thereby stabilizing neuronal circuits. An evolving understanding of the mechanisms of synaptic strengthening and remodeling, such as the PirB/MHCI pathway, will pay off for Alzheimer disease research, with its increasing focus on synaptic stability and repair.
Also of interest to AD researchers, some basic research news this week proves for the first time that the strengthening of synapses in response to activity (long-term potentiation, LTP) accounts for learning. First discovered 30 years ago, LTP has been extensively correlated with learning and memory, but never actually observed in living and learning animals. In two independent papers in today’s issue of ScienceExpress, Mark Bear at Massachusetts Institute of Technology and Todd Sacktor at the SUNY Downstate Medical Center in Brooklyn, New York, remedy that deficiency, providing direct evidence that LTP is in fact the mechanism of learning and memory storage in the brain.
In the Shatz work, published online in Science on August 17, first author Josh Syken sought to find out how MHCI affected synaptic plasticity by looking for potential counter receptors that would be present on neighboring neurons and could engage the MHCI protein. They found the transmembrane protein, paired-immunoglobulin-like receptor-B (PirB) fit the bill: PirB mRNA and protein are widely expressed throughout the brain of mice, and on cultured neurons. PirB protein localized at or near synapses, and bound MHCI on neurons.
In the immune system, PirB regulates cell activation via association with the Shp1 and Shp2 phosphatases, and the same associations were observed in mouse brain. A knockout mouse, which lacked the transmembrane domain (PirBTM), failed to activate these signaling proteins. The PirBTM mouse had no obvious phenotype, but because their own previous work showed that MHCI knockout mice had specific abnormalities in synaptic connectivity and plasticity in vision pathways, the investigators looked more closely at the visual cortex.
By measuring neuronal activation, they found that patterning of the visual cortex was entirely normal, suggesting that PirB is not required for the changes in synaptic formation that occur in this region in response to early visual stimulation. However, when the mice were deprived of light in one eye, the PirB mutants displayed an enhanced ability to rearrange synaptic connections. This ability to adjust connections, called ocular dominance plasticity, is normally high during early development, and decreases with age. In the PirB mutants, however, plasticity was enhanced at all ages.
“Together, these experiments show that PirB is needed to restrict the ability of neuronal circuits to readjust synaptic connections in response to alterations in activity levels or balance of inputs,” the authors conclude. Like the MHCI knockouts, the PirB mutant mice appear to have enhanced the processes that strengthen synaptic connections. The mechanism of this enhancement could involve similar signaling pathways to those used by MHCI/PirB in the immune system, where they modulate cytoskeletal proteins and integrin cell adhesion molecules, among others. In addition, the widespread expression of PirB suggests it may play a role in limiting synaptic plasticity outside of the visual system.
One function for synaptic plasticity throughout life is in learning. The process of long-term potentiation has been presumed to account for learning and memory, but until now, there was no hard evidence for it. Now, using two different approaches, two groups have provided the missing link between learning and LTP in rats. One report, from Mark Bear’s lab and Jonathan Whitlock of Brown University in Providence, Rhode Island, shows that training rats to avoid an electrical shock results in measurable LTP in the CA1 region of the hippocampus. Using multiple electrodes, they recorded in eight different areas, and found strengthened transmission at some electrodes in trained rats. The increased transmission was bona fide LTP, because when the scientists tried to induce LTP at the same locations with further electrical stimulation, they could not.
In the second report, the Sacktor group shows that maintaining memory depends on the persistence of LTP. Injection of a specific peptide inhibitor of protein kinase M ζ (PKM-ζ) into rat hippocampus inhibited the maintenance of LTP. The same inhibitor also disrupted spatial memory, since animals injected 24 hours after being trained to avoid an electric shock on a rotating platform behaved like untrained rats. The peptide, by blocking the maintenance of LTP, had erased their memory of the hazard.
The two papers “substantially advance the case for LTP as a neural mechanism for memory,” write Tim Bliss of the MRC National Institute for Medical Research in the U.K.; Graham Collingridge of the University of Bristol; and Serge Laroche of the University Paris Sud, in an accompanying commentary. The use of the PKM-ζ inhibitor, they say, opens up new opportunities to probe the function of LTP in different brain structures and in the various processes of learning, consolidation, and recall.—Pat McCaffrey.
Syken J, Grandpre T, Kanold PO, Shatz CJ. PirB Restricts Ocular-Dominance Plasticity in Visual Cortex. Science. 2006 Aug 17; [Epub ahead of print] Abstract
Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces long-term potentiation in the hippocampus. Science. 2006 Aug 25; [Epub ahead of print] Abstract
Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage of spatial information by the maintenance mechanism of LTP. Science. 2006 Aug 25; [Epub ahead of print] Abstract
Bliss TVP, Collingridge GL, Laroche S. ZAP and ZIP, a story to forget. Science. 2006 Aug 25; [Epub ahead of print] Abstract