Pre‐synaptic BK channels selectively control glutamate versus GABA release from cortical and hippocampal nerve terminals

Martire, Maria; Barrese, Vincenzo; D’Amico, Monia; Iannotti, Fabio Arturo; Pizzarelli, Rocco; Samengo, Irene Angela; Viggiano, D.; Ruth, Peter; Cherubini, Enrico; Taglialatela, Maurizio

doi:10.1111/j.1471-4159.2010.06938.x

Cited by 43 publications

(42 citation statements)

References 48 publications

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“…Nevertheless, BK channel activity is clearly intimately connected with seizure pathology. In fact, presynaptic BK channels have recently been shown to localize preferentially to and regulate neurotransmitter release at glutamatergic, but not GABAergic, synapses, further supporting their critical role in modulating circuit hyperexcitability (48). Whether FMRP/BK channel interactions are directly responsible for seizure and/or ID phenotypes and whether targeting BK channels could be a useful component of FXS therapy remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Myrick¹,

Deng²,

Hashimoto³

et al. 2015

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

107

132

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Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre-and postsynaptic defects, yet whether the pre-and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic-and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.F ragile X syndrome (FXS) is the most common single-gene disorder responsible for intellectual disability (ID) in patients (1). Along with cognitive dysfunction, the syndrome typically presents with several other comorbidities, including behavioral and social impairments (anxiety and autism spectrum disorder), neurological defects (seizures and abnormal sleep patterns), and morphological abnormalities (dysmorphic facies and macroorchidism). Most patients inherit the syndrome through a maternal repeat expansion mutation that transcriptionally silences the FMR1 gene and results in loss of the gene product, FMRP.FMRP has complex multifaceted functions at synapses both in pre-and postsynaptic compartments. As an RNA binding protein, FMRP is best known for its function as a translation regulator in dendrites (2). Loss of FMRP has been linked to various forms of long-term synaptic plasticity defects that depend on local protein synthesis in the postsynaptic neuron (3). In addition to disrupted metabotropic glutamate receptor signaling, which has been shown across multiple brain regions (4-7), FMRP is necessary for activitydependent protein synthesis downstream of other signaling receptor pathways, including ACh, dopamine, and TrkB (8-10).Although postsynaptic control of translation is believed to be the dominant function of FMRP, it is unable to explain all of the pathophysiology observed in FXS animal models. For instance, in Drosophila, presynaptic expression of the FMR1 homolog, dfmr1, completely rescues the synaptic overgrowth phenotype at the neuromuscular junction (NMJ) in dfmr1-null mutants (11-13). In rodent brain, FMRP has been found in structures called fragile-X granules, which are ...

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Section: Discussionmentioning

confidence: 99%

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Myrick¹,

Deng²,

Hashimoto³

et al. 2015

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

107

132

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“…Hippocampal glutamate and GABA containing SVs differ in their release properties during AP trains as well as in their adaptive response to strong depolarization (29)(30)(31). Different profiles of presynaptic ion channel expression underlie exocytosis in glutamatergic and GABAergic synapses (32)(33)(34). Our findings that greater isoflurane sensitivity of glutamatergic compared with GABAergic SV exocytosis is determined by larger effects on Ca 2+ influx are consistent with transmitter phenotype-specific differences in expression of the presynaptic ion channels that determine [Ca 2+ ] i , including distinct subtypes of Na v , Ca v , and K v channels (35).…”

Section: Discussionmentioning

confidence: 99%

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling

Baumgart

Zhou

Hara

et al. 2015

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

108

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Identifying presynaptic mechanisms of general anesthetics is critical to understanding their effects on synaptic transmission. We show that the volatile anesthetic isoflurane inhibits synaptic vesicle (SV) exocytosis at nerve terminals in dissociated rat hippocampal neurons through inhibition of presynaptic Ca 2+ influx without significantly altering the Ca 2+ sensitivity of SV exocytosis. A clinically relevant concentration of isoflurane (0.7 mM) inhibited changes in [Ca 2+ ] i driven by single action potentials (APs) by 25 ± 3%, which in turn led to 62 ± 3% inhibition of single AP-triggered exocytosis at 4 mM extracellular Ca 2+ ([Ca 2+ ] e ). Lowering external Ca 2+ to match the isoflurane-induced reduction in Ca 2+ entry led to an equivalent reduction in exocytosis. These data thus indicate that anesthetic inhibition of neurotransmitter release from small SVs occurs primarily through reduced axon terminal Ca 2+ entry without significant direct effects on Ca 2+ -exocytosis coupling or on the SV fusion machinery. Isoflurane inhibition of exocytosis and Ca 2+ influx was greater in glutamatergic compared with GABAergic nerve terminals, consistent with selective inhibition of excitatory synaptic transmission. Such alteration in the balance of excitatory to inhibitory transmission could mediate reduced neuronal interactions and network-selective effects observed in the anesthetized central nervous system. GCaMP3 | pHlourin | mechanisms of anesthesia | live cell imaging | presynaptic T he molecular and cellular mechanisms of anesthetic-induced amnesia, unconsciousness and immobilization are incompletely understood, particularly for the modern halogenated ether derivatives like isoflurane. General anesthetics, which are essential to both medical practice and experimental neuroscience, have potent and selective effects on neurotransmission (1), including both presynaptic actions (reduced neurotransmitter release) and postsynaptic actions (modulation of receptor function). These effects contribute to anesthetic-induced reductions in neuronal interactions, which are critical to information processing and consciousness (2-4). Knowledge of the fundamental synaptic effects of anesthetics is therefore essential to a molecular and physiological understanding of anesthetic mechanisms, and to development of more selective and safer anesthetics.Although postsynaptic electrophysiological effects of anesthetics can be assessed directly using whole cell recordings and heterologous expression of putative molecular targets, their presynaptic actions have been difficult to resolve by conventional approaches that do not clearly discriminate between presynaptic and postsynaptic contributions. Direct evidence for presynaptic effects of volatile anesthetics includes selective inhibition of glutamate release from isolated nerve terminals (5, 6) and of synaptic vesicle (SV) exocytosis in intact hippocampal neurons (7). However, it remains controversial whether these effects involve direct inhibition of SV exocytosis itself or of upstrea...

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“…K ca1.1 has a wide distribution in central nervous system, and prominent expression is observed in excitatory neurons of cortex and hippocampus. It plays vital roles in driving action potential repolarization, mediating fast phase of AHP (after hyperpolarization potential), and regulating neurotransmitter release and dendritic excitability [1][2][3].…”

Section: Discussionmentioning

confidence: 99%

“…K ca1.1 has a wide distribution in central nervous system, especially in excitatory neurons of cortex and hippocampus. It plays important roles in regulating neuronal excitability [1][2][3]. In 2005, KCNMA1 gene was first reported as a pathogenic gene in a large family with autosomal dominant paroxysmal nonkinesigenic dyskinesia and generalized epilepsy [4].…”

Section: Introductionmentioning

confidence: 99%

KCNMA1 mutation in children with paroxysmal dyskinesia and epilepsy: Case report and literature review

Wang

Zhang

et al. 2017

TRD

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Abstract.Patients with KCNMA1 gene mutation present with paroxysmal dyskinesia and/or epilepsy. We describe a male with heterozygous mutation c.3158A>G, (p.N1053S) in KCNMA1 gene, displaying paroxysmal dyskinesia and moderate mental retardation. We also review 20 reported cases with KCNMA1 mutation. We summarize that there is clinical heterogeneity in these patients. The onset age of episodic events ranges from 20 days to 15 years old. 6/21 (29%) patients merely had epilepsy, 10/21(48%) patients had paroxysmal dyskinesia only, and 5/21 (24%) had both epilepsy and paroxysmal dyskinesia. Seizure types were various, including absence, generalized tonic-clonic seizures, and myoclonic seizures. Paroxysmal dyskinesia was nonkinesigenic, but can be induced by alcohol, fatigue or stress. Most patients had variable degrees of mental retardation. The clinical outlook for this condition is in general not good. Epilepsy or non-epileptic events were resistant in most patients. Most patients presented with mild to severe intellectual disability and developmental delay.

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Pre‐synaptic BK channels selectively control glutamate versus GABA release from cortical and hippocampal nerve terminals

Cited by 43 publications

References 48 publications

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling

KCNMA1 mutation in children with paroxysmal dyskinesia and epilepsy: Case report and literature review

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Pre‐synaptic BK channels selectively control glutamate versus GABA release from cortical and hippocampal nerve terminals

Cited by 43 publications

References 48 publications

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca 2+ influx, not Ca 2+ -exocytosis coupling

KCNMA1 mutation in children with paroxysmal dyskinesia and epilepsy: Case report and literature review

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Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling