The studies being performed in the Sanes laboratory are laying the groundwork for development of future therapeutics and clinical solutions related to neurobiology. The laboratory focuses on molecular and cellular mechanisms of information processing in the brain by studying specific synaptic connections in normal developing animals and in mouse models of brain disease, and in aging mice. Their studies of normal and abnormal synaptic assembly and disassembly present commercial opportunities in multiple fields.

Several experimental approaches used in the lab could be developed as potential platform for pharmaceutical discovery. The laboratory has generated mouse models of motor system and visual system diseases. These transgenic mice enable visualization of neurons and their connection and provide valuable tools for testing and developing drugs.

To address the questions of cellular basis of age-related changes they have studied potential alterations in synapses using the skeletal neuromuscular junction (NMJ) formation. The results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes. Because these synaptic changes underlie age-related defects in neural function, one might look to synapses as targets for treatments that minimize or perhaps reverse the decline associated with aging. Well studied NMJ model promises to be a useful tool for assessing roles of known molecules such as sirtuins and insulin-like growth factors, as well as the discovery of novel factors and molecules which might regulate or attenuate age-related synaptic changes.

Another synaptic model system the laboratory has been developing is the photoreceptor synapse of the retina. This synapse undergoes dramatic age-related alterations. Current studies are elucidating the molecular bases of these alterations. This work provides potential targets for therapeutic interference in the disease states that affect vision.

• Investigate the mechanisms underlying formation and maintenance of the skeletal neuromuscular junction during development and following injury.
• Elucidate cellular and molecular bases of neuromuscular degeneration in age-related sarcopenia and neurodegenerative diseases such as ALS.
• Study the machinery responsible for formation of the retinal cells synapses and communication with the brain.
• Develop novel transgenic methods for visualizing synapse formation and synaptic circuits in live animals over time.

Brainbow mice: A set of fluorescent protein transgenic mice whose neurons have the potential to display every color of the rainbow.  Depending on the type of analysis used, over 89-166 colors may be distinguished. This, in turn, allows the unambiguous identification and tracing of multiple cells within a neuron ensemble, a critical step toward mapping the ''connectome''. Such wiring diagrams should lead to better understanding of diseases such as autism and schizophrenia, as well as new insight into learning and other cognitive functions.

More information about Brainbow mice can be found here:

• http://news.harvard.edu/gazette/story/2007/10/researchers-create-colorful-brainbow-images-of-the-nervous-system/ 
• Brainbow mice: A technicolor approach to map the neuronal circuits

Learn more about the Connectome project at the Center of Brain Science of Harvard University.

http://cbs.fas.harvard.edu/science/connectome-project

Sanes has been an international leader in analysis of the cellular and molecular mechanisms that underlie synapse formation in the vertebrate nervous system. Defects in synapse formation are likely to underlie many neurological and psychiatric diseases, and age-related decline in mental function is likely to reflect in part a disassembly of synapses.

For studies of synaptic differentiation, they use the skeletal neuromuscular junction (NMJ), because it is the best studied of all synapses and therefore a good subject for molecular analysis. The goal is to identify components that mediate intercellular interactions between pre- and postsynaptic cells. To identify functionally critical components, they combine studies of cultured cells and molecular genetic analysis of knockout mice. A current focus is to ask how neuromuscular synapses are stably maintained for much of the animal's life but then disassemble late in life. Changes in old age may lead to the clinically significant muscle wasting caused sarcopenia, and changes in neurodegenerative diseases such as ALS lead to paralysis and death. Recent studies from the Sanes lab show that two life-style regimens known to slow age-related cognitive decline, exercise and caloric restriction, act in part by attenuating such synaptic changes.

To learn how neurons recognize appropriate partners and assemble into circuits, the group has chosen to study the retinotectal projection. The Sanes laboratory is studying how retinal cells receive and make synapses in specific laminae of the eye and brain, respectively. Such laminar restrictions are major determinants of specific connectivity in many parts of the brain, including the cerebral cortex. The retina is a bona fide part of the brain, but is more accessible and better understood than cortex. It therefore serves as a good system for mechanistic analysis. In collaboration with Markus Meister, they are correlating molecular and histological features of retinal cell types with their functional properties. They are now using what they have learned both to analyze age-related changes in central synapses, and to assess wiring defects in mouse models of behavioral disorders.

In collaboration with the Lichtman Laboratory, the Sanes’ group devises novel transgenic methods for visualizing synapse formation and synaptic circuits in live animals over time. They have used these mice to image changes that occur in aging and in disease models. In addition, these visualizing methods aid in mapping cellular effects of the molecules identified in the other projects.

Thick bunches of nerves leave the brain or spinal cord and branch intricately within muscle. The image shows individual axons (yellow) connecting to single synapses (red). The red stain is a snake venom that binds only to muscle receptors. See Valdez G. et al, 2010, Proc Natl Acad Sci U S A. 107(33):14863-8 for more details. http://news.harvard.edu/gazette/story/2010/08/insights-on-healthy-aging/

Biological Mechanisms and Pathways

• Aging •
• Cell adhesion •
• Cell adhesion •
• Extracellular matrix •
• Neurobiology •
• Neuromuscular junction •
• Retina •
• Synapse •
• Vision
•  

Central Nervous System

• Motor neuron •
• Neural development •
• Neuromuscular junction
•  

Disease Mechanisms

• Neurological disease
•  

Metabolism; Metabolic Disease and Aging

• Aging
•  

Research Tools and Instrumentation

• Cell-based assays •
• Molecular modeling •
• Molecular modeling •
• Tissue engineering •
• Tissue engineering •
• Transgenic mice
•