Genetic Analysis of Glutamate Receptors in Drosophila Reveals a Retrograde Signal Regulating Presynaptic Transmitter Release

Petersen, Sophie A; Fetter, Richard D.; Noordermeer, Jasprina N.; Goodman, Corey S.; DiAntonio, Aaron

doi:10.1016/s0896-6273(00)80415-8

Cited by 444 publications

(727 citation statements)

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“…It has been established that glutamate has a primary role in neuromuscular transmission of organisms phylogenically distant from mammals, such as invertebrates, including insects and mollusks (22,49,50). In addition, glutamate acts as cotransmitter of ACh by regulating the development and function of cholinergic synapse in fishes and amphibians (51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle

Brunelli

Spano

Barlati

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Acetylcholine is the main neurotransmitter at the mammalian neuromuscular junction (NMJ) where nicotinic acetylcholine receptors mediate the signaling between nerve terminals and muscle fibers. We show that under glutamatergic transmission, rat NMJ switches from cholinergic type synapse to glutamatergic synapse. Connecting skeletal muscle to the lateral white matter of the spinal cord by grafting the distal stump of the transected motor nerve produced functional muscle reinnervation. The restored neuromuscular activity became resistant to common curare blockers but sensitive to the glutamate ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. Analysis of the regenerated nerve disclosed new glutamatergic axons and the disappearance of cholinergic fibers. Many axons belonged to the supraspinal neurons located in the red nucleus and the brainstem nuclei. Finally, the innervated muscle displayed high expression and clustering of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits glutamate receptors 1 and 2. Our data suggest that supraspinal neurons can target skeletal muscle, which retains the plasticity to generate functional glutamatergic NMJ.glutamate ͉ neuromuscular junction ͉ red nucleus T raumatic paraplegia caused by spinal cord injury is still an irreversible condition. So far, there is no medical or surgical treatment capable of curing paraplegia. The CNS is ''nonpermissive'' for the advancement of injured axons because of an abundance of growth-inhibitory molecules in the myelin and the glial scar (1-3). In addition, there are no growth-promoting factors at the neuronal growth cone or at the somata. However, when peripheral nerves (PN) are directly grafted into the CNS, central axons can progress throughout the peripheral endoneural tubes, suggesting they can regenerate in an appropriate environment (4-7). The central fibers that are diverted into a nerve graft implanted within a healthy structure derive from neurons axotomized during the grafting procedure and not from uninjured neurons spared by nerve graft implantation (8). Regrowth ceases as soon as axons contact the CNS milieu again. Various studies have demonstrated that central axons can elongate within autologous PN grafted into the spinal cord and form functional synapses with skeletal muscles, leading to motor and sensory recovery (7, 9-11). Spinal cord neurons, as well as the midbrain and brainstem neurons that originate the rubrospinal, vestibulospinal, and reticulospinal tracts, are endowed with a high capability of axonal regeneration into PN transplants (12-15). Thus, in an attempt to bypass a spinal cord lesion by connecting descending motor fibers with skeletal muscles, muscular nerve branches were inserted into the severed lateral bundle of monkey spinal cord (11). The new connection produced muscle reinnervation and restored motor function. This result raised the possibility that the regrowth of axons descending from central noncholinergic neurons and cut during the grafting procedure could be re...

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Section: Discussionmentioning

confidence: 99%

Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle

Brunelli

Spano

Barlati

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Specifically, decreased nonvesicular glutamate release resulted in increased expression of postsynaptic glutamate receptors (Featherstone et al, 2002), an effect recently linked to cystine-glutamate exchange (Augustin et al, 2007). Interestingly, postsynaptic glutamate receptor expression influences synapse morphology and presynaptic neurotransmitter release in Drosophila (Petersen et al, 1997;Sigrist et al, 2000). Nonvesicular glutamate release has also been shown to regulate cortical neuron migration during neurodevelopment (Manent et al, 2005).…”

Section: Cystine-glutamate Exchange and Schizophreniamentioning

confidence: 99%

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Baker

Madayag

Kristiansen

et al. 2007

Neuropsychopharmacol

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Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine-glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by Nacetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystineglutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine-glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine-glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP.

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“…Some molecular factors support such adjustments (3,4) and some physiological mechanisms have been proposed, such as changes in postsynaptic receptor composition (5,6). Work at the neuromuscular junction has uncovered other forms of synaptic homeostasis whereby purely postsynaptic interventions cause alterations in presynaptic function (3,4,7,8). However, no clear picture has emerged of the underlying molecular mechanisms that control presynaptic homeostasis.…”

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confidence: 99%

Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca ²⁺ entry pathway

Piedras-Renterı́a

Pyle

Diehn

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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At central synapses, P͞Q-type Ca 2؉ channels normally provide a critical Ca 2؉ entry pathway for neurotransmission. Nevertheless, we found that nerve terminals lacking ␣1A (CaV2.1), the pore-forming subunit of P͞Q-type channels, displayed a remarkable preservation of synaptic function. Two consistent physiological changes reflective of synaptic homeostasis were observed in cultured hippocampal neurons derived from ␣1A (؊/؊) mice. First, the presynaptic response to an ionophore-mediated Ca 2؉ elevation was 50% greater, indicating an enhanced Ca 2؉ sensitivity of the release machinery. Second, basal miniature excitatory postsynaptic current frequency in ␣1A (؊/؊) neurons was increased 2-fold compared with WT neurons and occluded the normal response of presynaptic terminals to cAMP elevation, suggesting that the compensatory mechanism in ␣1A (؊/؊) synapses and the modulation of presynaptic function by PKA might share a final common pathway. We used cDNA microarray analysis to identify molecular changes underlying homeostatic regulation in the ␣1A (؊/؊) hippocampus. The 40,000 entries in our custom-made array included likely targets of presynaptic homeostasis, along with many other transcripts, allowing a wide-ranging examination of gene expression. The developmental pattern of changes in transcript levels relative to WT was striking; mRNAs at 5 and 11 days postnatal showed little deviation, but clear differences emerged by 22 days. Many of the transcripts that differed significantly in abundance corresponded to known genes that could be incorporated within a logical pattern consistent with the modulation of presynaptic function. Changes in endocytotic proteins, signal transduction kinases, and candidates for Ca 2؉ -sensing molecules were consistent with implications of the direct physiological experiments.

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Genetic Analysis of Glutamate Receptors in Drosophila Reveals a Retrograde Signal Regulating Presynaptic Transmitter Release

Cited by 444 publications

References 50 publications

Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle

Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca ²⁺ entry pathway

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Genetic Analysis of Glutamate Receptors in Drosophila Reveals a Retrograde Signal Regulating Presynaptic Transmitter Release

Cited by 444 publications

References 50 publications

Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle

Glutamatergic reinnervation through peripheral nerve graft dictates assembly of glutamatergic synapses at rat skeletal muscle

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca 2+ entry pathway

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Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca ²⁺ entry pathway