An essential role for vesicular glutamate transporter 1 (VGLUT1) in postnatal development and control of quantal size
Sonja M. WojcikJeong Seop RheeÉtienne HerzogAlbrecht SiglerReinhard JahnShigeo TakamoriNils BroseChristian Rosenmund
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Abstract:
Quantal neurotransmitter release at excitatory synapses depends on glutamate import into synaptic vesicles by vesicular glutamate transporters (VGLUTs). Of the three known transporters, VGLUT1 and VGLUT2 are expressed prominently in the adult brain, but during the first two weeks of postnatal development, VGLUT2 expression predominates. Targeted deletion of VGLUT1 in mice causes lethality in the third postnatal week. Glutamatergic neurotransmission is drastically reduced in neurons from VGLUT1-deficient mice, with a specific reduction in quantal size. The remaining activity correlates with the expression of VGLUT2. This reduction in glutamatergic neurotransmission can be rescued and enhanced with overexpression of VGLUT1. These results show that the expression level of VGLUTs determines the amount of glutamate that is loaded into vesicles and released and thereby regulates the efficacy of neurotransmission.Keywords:
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Intercellular information transfer in the nervous system is mediated by chemical neurotransmitters. The fidelity of this process requires the rapid release and clearance of the neurotransmitter from the synaptic cleft. In addition to metabolic pathways for synthesis of neurotransmitters, two specific mechanisms, vesicular storage and local reuptake, have evolved to facilitate neurotransmission. These processes are mediated by transporter proteins: vesicular neurotransmitter transporters to fill the vesicles and plasma membrane neurotransmitter transporters to clear the synaptic cleft. This chapter discusses the synthesis, packaging, and recycling of the classic neurotransmitters with an emphasis on the transporter proteins that are integral to these pathways.
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Abstract The discovery of a new neurotransmitter, especially one in the central nervous system (CNS), is both important and difficult. We have been searching for new neurotransmitters for 12 years. We detected creatine (Cr) in synaptic vesicles (SVs), at a level lower than glutamate (Glu) and gamma-aminobutyric acid (GABA) but higher than acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (AGAT, a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability (ID) in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in SLC6A8 and AGAT mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP dependent manner. Our biochemical, chemical, genetic and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.
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Neurotransmitter release relies on a series of synaptic vesicle trafficking reactions. We have determined the molecular basis of these reactions by microinjecting, into ‘giant’ nerve terminals of squid, probes that interfere with presynaptic proteins. These probes affect neurotransmitter release and disrupt nerve terminal structure. From the nature of these lesions, it is possible to deduce the roles of individual proteins in specific vesicle trafficking reactions. This approach has revealed the function of more than a dozen presynaptic proteins and we hypothesize that neurotransmitter release requires the coordinated action of perhaps 50–100 proteins.
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The review include actual facts, demonstrating high probability of glutamatergic neurotransmitter system role in the regulation of the gastrointestinal tract motor activity. These facts suggest significant role of the glutamatergic neurotransmitter system dysfunction in forming motor activity disorders of the digestive tract, including in patients in critical condition. The analysis is based on results of multiple experimental and clinical researches of glutamic acid and other components of the glutamatergic neurotransmitter system in central nervous system and autonomic nervous system (with the accent on the enteral nervous system) in normal conditions and with functioning changes of the glutamatergic neurotransmitter system in case of inflammation, hupoxia, stress and in critical condition.
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The discovery of a new neurotransmitter, especially one in the central nervous system (CNS), is both important and difficult. We have been searching for new neurotransmitters for 12 years. We detected creatine (Cr) in synaptic vesicles (SVs), at a level lower than glutamate (Glu) and gamma-aminobutyric acid (GABA) but higher than acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (AGAT, a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability (ID) in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in SLC6A8 and AGAT mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP dependent manner. Our biochemical, chemical, genetic and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter.Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.
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