Different Presynaptic Roles of Synapsins at Excitatory and Inhibitory Synapses

Gitler, Daniel; Takagishi, Yoshiko; Feng, Jian; Ren, Yong; Rodriguiz, Ramona M.; Wetsel, William C.; Greengard, Paul; Augustine, George J

doi:10.1523/jneurosci.3795-04.2004

Cited by 309 publications

(458 citation statements)

References 73 publications

Supporting

Mentioning

408

Contrasting

Order By: Relevance

“…The increase in docked vesicles on Munc18 overexpression may be a consequence of the increased total number of vesicles in the terminal. However, in previous studies, changes in total vesicle number did not lead to concomitant changes in the number of docked vesicles (5,36), and Munc18 overexpression in chromaffin cells also increased docking but without affecting total vesicle numbers (37). Hence, often docking does not correlate with the total number of available vesicles, presumably because of the limited availability of docking sites.…”

Section: Discussionmentioning

confidence: 80%

Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size

Toonen¹,

Wierda

Sons

et al. 2006

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

160

155

View full text Add to dashboard Cite

Prompt recovery after intense activity is an essential feature of most mammalian synapses. Here we show that synapses with reduced expression of the presynaptic gene munc18-1 suffer from increased depression during intense stimulation at glutamatergic, GABAergic, and neuromuscular synapses. Conversely, munc18-1 overexpression makes these synapses recover faster. Concomitant changes in the readily releasable vesicle pool and its refill kinetics were found. The number of vesicles docked at the active zone and the total number of vesicles per terminal correlated with both munc18-1 expression levels and the size of the releasable vesicle pool. These data show that varying expression of a single gene controls synaptic recovery by modulating the number of docked, release-ready vesicles and thereby replenishment of the secretion capacity.autapse ͉ docking ͉ exocytosis ͉ secretion ͉ synaptic transmission R eliable and sustainable neurotransmitter release is essential for effective neuronal communication. However, neurons only have a limited number of fusion-ready vesicles that reside in a vesicle pool at the membrane of the presynaptic terminal (1). During periods of increased activity, this vesicle pool is depleted, resulting in a decreased reliability of neurotransmission. To ensure efficient neurotransmission, neurons need to be able to increase the initial number of fusion-ready vesicles [the so-called readily releasable pool (RRP)] and͞or the rate at which this pool is replenished during activity. However, surprisingly little is known about the molecular mechanisms that control the size of the RRP and the way vesicles are recruited to this pool.The Sec1͞Munc18-like (SM) protein Munc18-1 has emerged as a key component for calcium-dependent neurotransmitter release (2). SM proteins function in all intracellular membrane trafficking pathways across species. Genetic deletion of Munc18-1 and most other SM genes involved in synaptic-vesicle release across species results in a complete block of neurotransmitter release (3-5), which shows that Munc18-1 and probably all SM proteins are indispensable factors that promote vesicle secretion (2, 6, 7). However, identifying where SM proteins act in the cascade of events leading to the release of neurotransmitter has proven to be difficult and has generated apparently conflicting data (8-10).Here, we analyzed the effect of different Munc18-1 expression levels on synaptic function in autaptic synapses of GABAergic and glutamatergic central neurons, as well as in the peripheral neuromuscular junction (NMJ). We combined electrophysiological and optical measurements to show that Munc18-1 controls synapse efficacy in a bidirectional way via the control of the size and replenishment rate of the RRP. ResultsIn homozygous munc18-1-null mutant mice, synapses are silent (3), identifying munc18-1 as an essential gene but providing little information on its molecular function. Heterozygous mice (munc18-1 ϩ/Ϫ ) had a 50% reduction of Munc18-1 protein expression but no reduction in the levels ...

show abstract

Section: Discussionmentioning

confidence: 80%

Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size

Toonen¹,

Wierda

Sons

et al. 2006

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

160

155

View full text Add to dashboard Cite

show abstract

“…In particular, there is a loss of immediately releasable GABA, which could account for the hyperexcitability. 365,366 The synapsins are regulated by phosphorylation, which might provide a mechanism for pharmacological manipulation.…”

Section: Synaptic Vesicle Proteinsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

View full text Add to dashboard Cite

Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

show abstract

“…Defining the potential role of ethanol action on nicotinic receptor influences on GABA transmission could be a means to understand the high incidence of nicotine addiction in alcoholics. Missing from consideration is testing the effect of ethanol on the myriad of other neurotransmitters and mechanisms that appear to influence presynaptic release of GABA (Cossart et al, 2001;Gitler et al, 2004;Ho et al, 2003;Kerchner et al, 2001;Meir et al, 1999;Miller, 1998;Nakamura et al, 2003;Saitow et al, 2001;Satake et al, 2000).…”

Section: Other Presynaptic Receptor Involvementmentioning

confidence: 99%

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Neuropsychopharmacol

View full text Add to dashboard Cite

Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.

show abstract

Different Presynaptic Roles of Synapsins at Excitatory and Inhibitory Synapses

Cited by 309 publications

References 73 publications

Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size

Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size

Molecular Targets for Antiepileptic Drug Development

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Contact Info

Product

Resources

About