Title

Control of microglial cell migration

Date of Award

2004

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Physiology and Biophysics

First Committee Member

Kenneth J. Muller, Committee Chair

Abstract

Information about the signals that regulate microglia activation and movement is incomplete. Nitric oxide (NO) generated immediately after injury was found previously in the leech central nervous system (CNS) to stop microglia migration at lesions. Questions addressed in the present study were (1) Does removing NO affect microglia migration in response to injury? (2) Does NO generated by injury work by activating soluble guanylate cyclase (sGC) to produce cyclic GMP (cGMP)? (3) In what ways does cGMP influence microglia migration? and (4) Does NO or a different molecule activate microglial cells to move?Chapter I and II show that injury induces a cGMP immunoreactivity at the lesion site which matches the distribution of increased eNOS immunoreactivity and accumulation of microglia at the lesion. The NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetram ethyl imidazoline-oxyl-3-oxide (cPTIO) and the sGC inhibitors LY 83583 and methylene blue (MB) affect microglia migration and accumulation at the lesion. cPTIO and LY 83583 and MB reduced cGmp immunoreativity and microglial cell accumulation at the lesions. Time lapse video microscopy of microglia in living nerve cords showed that both 1 mM cPTIO and 20 muMLY 83583 and muM MB did not reduce cell movement but reduced directed movement. NO, therefore, can direct microglia movement after injury by activating the production of cGMP.Chapter III describes a mechanism that triggers microglial cell movement. Extracellular nucleotides including ATP, ADP and UTP enhanced the basal movement of microglial cells. Reactive blue 2 (RB2), an antagonist for P2Y receptors of extracellular nucleotides, blocked microglial cell accumulation at the lesion by blocking cell movement.The migration of microglial cells, therefore, is regulated in different ways by both NO and extracellular ATP. ATP triggers their movement while NO guides their direction by suppressing misdirected movement through the production of cGMP.

Keywords

Biology, Neuroscience; Biology, Animal Physiology

Link to Full Text

http://access.library.miami.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3159157