Proper nervous system function critically depends on the proper assembly, maintenance, and activity- dependent modification of neuronal circuits. Although a great deal is known about extracellular molecules and signaling pathways that regulate axonal growth and pathfinding during embryonic nervous system development, comparatively little is known about the mechanisms that control synaptic structure and function in the juvenile and adult mammalian brain and spinal cord. Mounting evidence suggests that there is a close overlap of molecular players that limit neuronal sprouting in the injured CNS, and molecules that restrict neuronal plasticity in the healthy (uninjured) CNS. Recent studies from our lab revealed that the growth inhibitory proteins Nogo/RTN4 and oligodendrocyte myelin glycoprotein (OMgp) suppress activity-dependent synaptic plasticity in an NgR1-dependent manner. The signaling mechanisms employed by NgR1 to regulate synaptic structure and synaptic transmission have not yet been defined. This research will pursue mouse genetic, primary neuronal cell culture, and biochemistry-based approaches to define the signaling pathways regulated downstream of Nogo/NgR1, with a primary focus on the PI3K/AKT/mTORC1 pathway. In a parallel approach, a combination of electrophysiological recordings and pharmacological treatments will be used to examine the molecular mechanisms underlying the previous observations that loss of NgR1 attenuates LTD at CA3-CA1 synapses, and that application of Nogo66 decreases LTP of synaptic transmission in CA1 neurons. Behavioral studies in NgR1 germline and conditional mutants will assess the importance of NgR1 signaling in learning and memory. Because changes in neuronal structure and synaptic function often correlate with brain disease, a detailed understanding of how brain structure and function is regulated is of great interest, both biologically and clinically. Experiments proposed are a systematic analysis of Nogo receptor function, and are expected to provide insights into key aspects of nervous system physiology and pathology.

Public Health Relevance

Most of our knowledge on myelin inhibitors and their receptors is based on studies of the injured adult mammalian CNS. A key gap in our knowledge is the role of these molecules in the healthy (uninjured) CNS. Recent evidence suggests that Nogo and its receptors are important regulators of synaptic structure and synaptic function. Here we propose research to examine the molecular mechanisms employed by Nogo and Nogo receptors to regulate synaptic function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS081852-01A1
Application #
8594705
Study Section
Special Emphasis Panel (ZRG1-F03A-N (20))
Program Officer
Mamounas, Laura
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2013-12-01
Budget End
Support Year
1
Fiscal Year
2013
Total Cost
$32,725
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109