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Transgenic overexpression of the presynaptic choline transporter elevates acetylcholine levels and augments motor endurance.
Holmstrand EC, Lund D, Cherian AK, Wright J, Martin RF, Ennis EA, Stanwood GD, Sarter M, Blakely RD
(2014) Neurochem Int 73: 217-28
MeSH Terms: Acetylcholine, Animals, Behavior, Animal, Choline, Cholinergic Agents, Chromosomes, Artificial, Bacterial, Gene Dosage, Hemicholinium 3, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Physical Endurance, Receptors, Presynaptic, Synaptosomes
Show Abstract · Added December 2, 2013
The hemicholinium-3 (HC-3) sensitive, high-affinity choline transporter (CHT) sustains cholinergic signaling via the presynaptic uptake of choline derived from dietary sources or from acetylcholinesterase (AChE)-mediated hydrolysis of acetylcholine (ACh). Loss of cholinergic signaling capacity is associated with cognitive and motor deficits in humans and in animal models. Whereas genetic elimination of CHT has revealed the critical nature of CHT in maintaining ACh stores and sustaining cholinergic signaling, the consequences of elevating CHT expression have yet to be studied. Using bacterial artificial chromosome (BAC)-mediated transgenic methods, we generated mice with integrated additional copies of the mouse Slc5a7 gene. BAC-CHT mice are viable, appear to develop normally, and breed at wild-type (WT) rates. Biochemical studies revealed a 2 to 3-fold elevation in CHT protein levels in the CNS and periphery, paralleled by significant increases in [(3)H]HC-3 binding and synaptosomal choline transport activity. Elevations of ACh in the BAC-CHT mice occurred without compensatory changes in the activity of either choline acetyltransferase (ChAT) or AChE. Immunohistochemistry for CHT in BAC-CHT brain sections revealed markedly elevated CHT expression in the cell bodies of cholinergic neurons and in axons projecting to regions known to receive cholinergic innervation. Behaviorally, BAC-CHT mice exhibited diminished fatigue and increased speeds on the treadmill test without evidence of increased strength. Finally, BAC-CHT mice displayed elevated horizontal activity in the open field test, diminished spontaneous alteration in the Y-maze, and reduced time in the open arms of the elevated plus maze. Together, these studies provide biochemical, pharmacological and behavioral evidence that CHT protein expression and activity can be elevated beyond that seen in wild-type animals. BAC-CHT mice thus represent a novel tool to examine both the positive and negative impact of constitutively elevated cholinergic signaling capacity.
Copyright © 2013 Elsevier Ltd. All rights reserved.
1 Communities
2 Members
0 Resources
15 MeSH Terms
All aglow about presynaptic receptor regulation of neurotransmitter transporters.
Blakely RD, DeFelice LJ
(2007) Mol Pharmacol 71: 1206-8
MeSH Terms: Extracellular Signal-Regulated MAP Kinases, Humans, Neurotransmitter Transport Proteins, Pyridinium Compounds, Receptors, Presynaptic, Spectrometry, Fluorescence
Show Abstract · Added July 10, 2013
Mounting evidence supports the idea that neurotransmitter transporters are subject to many forms of post-translational regulation typically associated with receptors and ion channels, including receptor and kinase-mediated changes in transporter phosphorylation, cell surface trafficking, and/or catalytic activation. Although hints of this regulation can be achieved with traditional radiolabeled substrate flux techniques, higher resolution methods are needed that can localize transporter function in situ as well as permit real-time monitoring of transport function without confounds associated with coincident receptor activation. The elegant study by Bolan et al. (p. 1222) capitalizes on the fluorescent properties of a recently introduced substrate for the dopamine (DA) transporter (DAT), termed 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+), to illuminate a pertussis toxin-sensitive, extracellular signal-regulated kinase (ERK1/2)-dependent pathway by which presynaptic DA D(2) receptors regulate DATs.
1 Communities
1 Members
0 Resources
6 MeSH Terms
Coordinate regulation of metabotropic glutamate receptors.
Alagarsamy S, Sorensen SD, Conn PJ
(2001) Curr Opin Neurobiol 11: 357-62
MeSH Terms: Animals, Brain, Cells, Cultured, Cyclic AMP-Dependent Protein Kinases, Glutamic Acid, Humans, Nerve Tissue Proteins, Phosphorylation, Protein Kinase C, Protein Processing, Post-Translational, Protein Subunits, Receptor Cross-Talk, Receptors, Metabotropic Glutamate, Receptors, N-Methyl-D-Aspartate, Receptors, Presynaptic, Signal Transduction
Show Abstract · Added February 19, 2015
Recent studies aimed at identifying the mechanisms that regulate the signaling of metabotropic glutamate receptors (mGluRs) have revealed that both protein kinase and protein phosphatase activity are important in directly modulating mGluR function. The inter-relationship between phosphorylation and dephosphorylation of mGluRs seems to be an important determinant in regulating mGluR function and the subsequent neuromodulatory events elicited by activation of mGluRs.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Activation of group III mGluRs inhibits GABAergic and glutamatergic transmission in the substantia nigra pars reticulata.
Wittmann M, Marino MJ, Bradley SR, Conn PJ
(2001) J Neurophysiol 85: 1960-8
MeSH Terms: 2-Amino-5-phosphonovalerate, 6-Cyano-7-nitroquinoxaline-2,3-dione, Action Potentials, Amino Acids, Aminobutyrates, Animals, Bicuculline, Drug Design, Electric Stimulation, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, GABA Antagonists, Glutamic Acid, Glycine, Kainic Acid, Nerve Tissue Proteins, Patch-Clamp Techniques, Phosphoserine, Rats, Rats, Sprague-Dawley, Receptors, AMPA, Receptors, GABA-A, Receptors, Metabotropic Glutamate, Receptors, Presynaptic, Substantia Nigra, Xanthenes, gamma-Aminobutyric Acid
Show Abstract · Added February 19, 2015
The GABAergic projection neurons of the substantia nigra pars reticulata (SNr) exert an important influence on the initiation and control of movement. The SNr is a primary output nucleus of the basal ganglia (BG) and is controlled by excitatory inputs from the subthalamic nucleus (STN) and inhibitory inputs from the striatum and globus pallidus. Changes in the output of the SNr are believed to be critically involved in the development of a variety of movement disorders. Anatomical studies reveal that metabotropic glutamate receptors (mGluRs) are highly expressed throughout the BG. Interestingly, mRNA for group III mGluRs are highly expressed in STN, striatum, and globus pallidus, and immunocytochemical studies have shown that the group III mGluR proteins are present in the SNr. Thus it is possible that group III mGluRs play a role in the modulation of synaptic transmission in this nucleus. We performed whole cell patch-clamp recordings from nondopaminergic SNr neurons to investigate the effect of group III mGluR activation on excitatory and inhibitory transmission in the SNr. We report that activation of group III mGluRs by the selective agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 100 microM) decreases inhibitory synaptic transmission in the SNr. Miniature inhibitory postsynaptic currents studies and paired-pulse studies reveal that this effect is mediated by a presynaptic mechanism. Furthermore we found that L-AP4 (500 microM) also reduces excitatory synaptic transmission at the STN-SNr synapse by action on presynaptically localized group III mGluRs. The finding that mGluRs modulate the major inputs to SNr neurons suggests that these receptors may play an important role in motor function and could provide new targets for the development of pharmacological treatments of movement disorders.
0 Communities
1 Members
0 Resources
27 MeSH Terms
Activation of group II metabotropic glutamate receptors inhibits synaptic excitation of the substantia Nigra pars reticulata.
Bradley SR, Marino MJ, Wittmann M, Rouse ST, Awad H, Levey AI, Conn PJ
(2000) J Neurosci 20: 3085-94
MeSH Terms: Animals, Bridged Bicyclo Compounds, Catalepsy, Dopamine Antagonists, Excitatory Amino Acid Agonists, Excitatory Postsynaptic Potentials, Glutamic Acid, Haloperidol, Male, Parkinson Disease, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Receptors, Presynaptic, Substantia Nigra, Subthalamic Nucleus
Show Abstract · Added February 19, 2015
Loss of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) leads to increased activity of glutamatergic neurons in the subthalamic nucleus (STN). Recent studies reveal that the resultant increase in STN-induced excitation of basal ganglia output nuclei is responsible for the disabling motor impairment characteristic of PD. On the basis of this, it is possible that any manipulation that reduces activity at excitatory STN synapses onto basal ganglia output nuclei could be useful in the treatment of PD. We now report that group II metabotropic glutamate receptors (mGluRs) are presynaptically localized on STN terminals and that activation of these receptors inhibits excitatory transmission at STN synapses. In agreement with the hypothesis that this could provide a therapeutic benefit in PD, a selective agonist of group II mGluRs induces a dramatic reversal of catalepsy in a rat model of PD. These results raise the exciting possibility that selective agonists of group II mGluRs could provide an entirely new approach to the treatment of PD. These novel therapeutic agents would provide a noninvasive pharmacological treatment that does not involve the manipulation of dopaminergic systems, thus avoiding the problems associated with current therapies.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Prenatal development of rat primary afferent fibers: II. Central projections.
Mirnics K, Koerber HR
(1995) J Comp Neurol 355: 601-14
MeSH Terms: Animals, Carbocyanines, Female, Fluorescent Dyes, Ganglia, Spinal, Hindlimb, Nerve Fibers, Neural Pathways, Neurons, Afferent, Pregnancy, Rats, Rats, Sprague-Dawley, Receptors, Presynaptic, Somatosensory Cortex, Spinal Cord
Show Abstract · Added February 12, 2015
These studies were designed to determine the pattern of initial afferent fiber ingrowth into the prenatal spinal gray matter and the establishment of the topographic organization of the presynaptic neuropil in the dorsal horn. A total of 113 lumbar dorsal root ganglia were labeled with carbocyanine fluorescent dye DiI or DiA in 67 rat embryos and neonatal pups aged embryonic day 13 to postnatal day 0 (E13-P0). The initial fiber penetration of the lumbar spinal gray began at E15 and was restricted to the segments of entry. Subsequent growth of fibers into gray matter of adjacent segments began approximately one day later, and this delay was continued, about one day for each successive segment. A second wave of ingrowth of putative small-diameter afferents into the substantia gelatinosa began at E19 and also displayed the same rostrocaudal delay. Fiber ingrowth was specific and occupied the somatotopic area appropriate for the adult, from the earliest stages (E18) in which dorsal horn laminae could be adequately defined. The somatotopic organization of the presynaptic neuropil in laminae III and IV did not change significantly throughout embryonic development as the amount of overlap between adjacent and non-adjacent ganglion projections remained constant throughout embryonic development. In addition, it was found that fibers innervating the proximal and distal hindlimb entered the spinal gray simultaneously at E15 before the innervation of the distal toes was established. The results of these studies indicate that the somatotopic organization of the presynaptic neuropil is established very early in development and requires little refinement to match that seen in the adult. The simultaneous penetration of the fibers originating from the proximal and distal areas of the limb before innervation is complete suggests that this ingrowth may be independent of the establishment of specific peripheral connections.
0 Communities
1 Members
0 Resources
15 MeSH Terms