Biomedical Sciences ETDs

Publication Date

7-1-2011

Abstract

Neurosteroids are compounds synthesized de novo within the central nervous system and affect brain function via genomic and non-genomic mechanisms. Sulfated neurosteroids modulate synaptic neurotransmission via interactions with various membrane receptors located at pre- and/ or postsynaptic sites, including metabotropic and ionotropic neurotransmitter receptors and ion permeable channels. The interactions of sulfated neurosteroids with these types of targets can induce rapid changes in neurotransmitter release and/or in postsynaptic responses. Since the 1940's, pregnenolone sulfate (PregS), the sulfated version of the steroid precursor, pregnenolone, has been suggested to have anti-stress, anti-aging, antidepressive, neuroprotective and memory enhancing effects in the mature brain. However, little is known on the physiological role of PregS in the development of the brain. Previous studies from our laboratory have postulated PregS as a novel enhancer of excitatory neurotransmission in the hippocampus, a brain area important for learning and memory. In the work presented here, we evaluated the effects of PregS in the developing rat cerebellum. The cerebellum is a brain region essential for motor coordiation, balance and equilibrium, muscle tone, and cognitive and language functions. We found that PregS potently and reversibly enhanced the release of the excitatory neurotransmitter, glutamate, onto neonatal Purkinje cells (PCs), which provide the sole output from the cerebellar cortex. This effect of PregS was present at the climbing-fiber-to-PC synapse, a powerful glutamatergic synapse important for the timing of conditioned reflexes. Interestingly, the mechanism responsible for this effect of PregS is mediated by a Ca2+ permeable cation channel, the transient receptor potential melastatin 3 (TRPM3) channel. This channel was recently shown to be sensitive to PregS and to be involved in a number of physiological events in the periphery. However, its role in brain physiology is unknown. Thus, the studies presented here postulate TRPM3 channels as novel modulators of excitatory neurotransmission in the immature brain. In addition, we found that TRPM3 channels are highly expressed in all layers of the developing cerebellar cortex. This finding suggests that these steroid-sensitive channels play a major role in the development of this brain region. Lastly, we found that pharmacologically-induced increases in endogenous PregS-like neurosteroids potentiate glutamatergic transmission at PCs in organotypic hindbrain cultures. This finding sets up the stage for future experiments that will investigate the effect of TRPM3 channels and endogenous PregS in the development of the cerebellar cortex.

Keywords

developing cerebellum, neurosteroid, pregnenolone sulfate, transient receptor potential melastatin 3

Sponsors

National Insitutes of Health Grants MH70386 and AA14973

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Valenzuela, Carlos Fernando

First Committee Member (Chair)

Partridge, Donald

Second Committee Member

Zhao, Xiny

Third Committee Member

Mueller, Wolfgang

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