The amino acids L-glutamate and γ-aminobutyric acid (GABA) have been primarily characterized as the most prevalent synaptic neurotransmitters, excitatory and inhibitory respectively, in the vertebrate central nervous system. However, the role of these signaling molecules extends far beyond the synapse. GABA, glutamate, and their complement of receptors are essential signaling molecules that regulate development in many regions of the central nervous system via non-synaptic mechanisms. Here I investigate the interrelated hypotheses that intercellular, non-synaptic glutamatergic signaling is present in the postnatal neurogenic forebrain and that the potential for GABA-ergic signaling exists in the cerebellar external germinal layer. In the cerebellum, perforated patch clamp recordings revealed that GABA depolarized granule cell precursors via GABAA receptors, which led to an increase in intracellular calcium. In the neurogenic forebrain, neuroblasts were shown to express functional NMDA-type glutamate receptors, the expression of which increases along the rostrocaudal axis of their migratory path to the postnatal olfactory bulb. Further recordings revealed that NMDA receptors are activated tonically by an endogenous source of glutamate and in vivo blockade of NMDA receptors induced an increase in apoptosis. To uncover the endogenous source of glutamate, we employed multiple techniques. Immunohistochemistry and electron microscopy showed that astrocytes in the neurogenic forebrain contain releasable glutamate and tonic NMDA receptor activity in neuroblasts was independent of action potentials and synaptic vesicular release. Both pharmacological and genetic manipulations of astrocytic intracellular calcium activity changed the degree of NMDA receptor activation. These results indicated that astrocytic release, not synaptic spillover, is the source of ambient glutamate. Further investigations into the mechanism of astrocytic release showed that blockade of vesicular refilling and vesicular release resulted in a block of tonic NMDA receptor activity. Collectively, these results identify a novel type of non-synaptic, vesicular glutamatergic signaling from astrocytes to neuroblasts. These findings suggest that astrocytes of the neurogenic forebrain create a microenvironment where they employ glutamate signaling through NMDARs to enhance neuroblast survival, therefore regulating the number of neuroblasts able to integrate into the olfactory bulb as mature granule neurons.
|School Location:||United States -- Connecticut|
|Source:||DAI-B 70/01, Dissertation Abstracts International|
|Keywords:||GABA, Glutamate, NMDA receptors, Neurogenesis, Subventricular zone|
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