New Scholar Award in Aging
University of Rochester Medical Center
Mechanisms of Neural Plasticity in the Mammalian System.
There is growing evidence that the molecular mechanisms that underlie the sculpting of neuronal networks during development
also apply to aspects of adult neuronal plasticity and repair. Several families of molecules that regulate axonal pathfinding in the
developing nervous system have been described. However, little is known about the function of these molecules in the mature
nervous system. To study the function of semaphorins, a conserved family of axon guidance molecules, in the mammalian
nervous system, we have recently generated mice that are mutant for the semaphorin receptor, neurophilin-2. Neurophilin-2 is
an essential component of the semaphorin receptor complex, binds secreted semaphorins with high affinity, and imparts
functional specificity toward select members of secreted semaphorins. Neurophilin-2 mutant mice are viable into adulthood and
display select neuronal defects.
We hypothesize that semaphorins and their receptors have specific functions in the mature nervous system related to synaptic
remodeling and axon regeneration. This is supported by the continued statement of semaphorins and their receptors in specific
regions of the mature nervous system; including structures that are critical for learning and memory. For example, strong
statement of semaphorins is observed in the hippocampal formation, the neocortex, thalamus, and the olfactory system.
Interestingly, semaphorin statement in the mature central nervous system is regulated following injury and upon electrical
stimulation. Furthermore, it has recently been shown that select populations of mature sensory neurons remain responsive to
semaphorins in vitro.
Using a genetic approach, combined with various cell culture paradigms, our research aims to elucidate the mechanisms that
govern the assembly and maintenance of specific neural circuitry. Understanding the molecular principles of network assembly
will have important implications for strategies of adult neural repair following trauma or disease.