Experience And Auditory Brainstem Development: Signals, Cellular Events And Critical Periods

Edwin W Rubel

Virginia Merrill Bloedel Hearing Research Center and Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA 98117, USA

Since the classic experiments of Hamburger, Levi-Montalcini, and Hubel & Wiesel, a large variety of studies have shown that manipulations of peripheral input and sensory experience can have profound influences on the development of sensory encoding pathways of the central nervous system. Yet, relatively little is known about the cellular mechanisms whereby changes in sensory system function influence the structure or integrity of CNS elements. We have used the brainstem auditory pathways of birds and mammals to investigate the early cellular events underlying deprivation- and deafferentation-induced changes in the structure and integrity of neurons and glial cells. I will discuss a series of in vivo and in vitro experiments that address three issues related to activity-regulated development and maintenance of cochlear nucleus neurons. What is the nature of the intercellular signals regulating structural integrity of postsynaptic neurons? What are some of the intracellular cascades of events underlying deprivation-induced changes in neuronal integrity? What biological mechanisms may underlie developmental differences in responses to peripheral manipulations (critical periods)?

To address the first question, a series of experiments were designed to independently manipulate patterned acoustic information, spontaneous eighth nerve activity, presynaptic stimulation and postsynaptic action potential generation. We were able to conclude that the necessary and sufficient condition for maintaining a normal compliment of cochlear nucleus neurons is stimulation of membrane-bound glutamate receptors. Studies of the dynamic cellular events subsequent to deprivation reveal disinhibition of a unique signaling pathway involving metabotrobic glutamate receptor regulation of intracellular calcium. A working model suggests that when ongoing activation of this pathway is interrupted, elevated intracellular calcium activates an apoptotic-like cascade resulting in rapid cell death or cell atrophy in the target neurons. Finally, recent experiments using normal and transgenic mice, and microarray technology have focused understanding the differential susceptibility of neonatal and adult sensory systems to deprivation of afferent activity (a critical period). I will present results indicating that downstream regulators of cell death can dramatically modulate the critical period response and that the switch from deprivation sensitive to deprivation insensitive probably involves the orchestrated changes transcription of many cell death regulatory genes. Support provided by NIDCD.