Regulation of Neurotransmitter Release by Synapsin III

Feng, Jian; Chi, Ping; Blanpied, Thomas A.; Xu, Yimei; Magariños, Ana Marı́a; Ferreira, Adriana; Takahashi, Riku; Kao, Hung‐Teh; McEwen, Bruce S.; Ryan, Timothy A.; Augustine, George J; Greengard, Paul

doi:10.1523/jneurosci.22-11-04372.2002

Cited by 142 publications

(163 citation statements)

References 39 publications

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“…The somewhat contrasting locomotor responses to amphetamine and methylphenidate in the CK1δ OE mice might indicate that the overexpression of CK1δ affects especially the presynaptic machinery to modulate neurotransmitter release. It is well established that protein phosphorylation can modulate neurotransmitter release (30,31). It has been found that purified synaptic vesicles from rat brain were highly enriched in CK1.…”

Section: Discussionmentioning

confidence: 99%

Forebrain overexpression of CK1δ leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD

Zhou

Rebholz²,

Brocia³

et al. 2010

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

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Dopamine neurotransmission controls motor and perseverative behavior, is mediated by protein phosphorylation, and may be perturbed in disorders of attention and hyperactivity. To assess the role of casein kinase I (CK1) in the regulation of dopamine signaling, we generated a genetically modified mouse line that overexpresses CK1δ (CK1δ OE) specifically in the forebrain. Overexpression was confirmed both at the mRNA and at the protein levels. Under basal conditions, CK1δ OE mice exhibited horizontal and vertical hyperactivity, reduced anxiety, and nesting behavior deficiencies. The CK1δ OE mice also presented paradoxical responses to dopamine receptor stimulation, showing hypoactivity following injection of d-amphetamine or methylphenidate, indicating that CK1 activity has a profound effect on dopamine signaling in vivo. Interestingly, CK1δ overexpression led to significantly reduced D1R and D2R dopamine receptor levels. All together, under basal conditions and in response to drug stimulation, the behavioral phenotype of CK1δ OE mice is reminiscent of the symptoms and drug responses observed in attention-deficit/hyperactivity disorder and therefore the CK1δ OE mice appear to be a model for this disorder.CK1 | D1R | methylphenidate | protein kinase amphetamine C asein kinase 1 (CK1) represents an evolutionarily conserved eukaryotic protein kinase family consisting of several isoforms including CK1δ, which is one of the most enriched in brain. The CK1 Ser/Thr kinase family plays a crucial role in numerous biological functions ranging from cell cycle regulation (1-5) to more complex behavioral traits (6-8). In the central nervous system, CK1δ is involved in a variety of physiological (e.g., cell signaling, circadian rhythm, cellular trafficking) and pathological (e.g., amyloid-β formation and tauopathies) processes (9-14). In the basal ganglia, CK1 regulates the state of phosphorylation of DARPP-32 (dopamine-and cAMP-regulated phospho-protein Mw of 32 kDa), a key striatal protein, which integrates synaptic input signals from various origins including the dopaminergic and glutamatergic systems (15-17). Imbalance of dopamine neurotransmission in the nigrostriatal pathway has been linked to various neurodevelopmental disorders, such as attention-deficit/ hyperactivity disorder (ADHD) (18)(19)(20)(21)(22). Indeed, the frontostriatal network has been largely implicated in the occurrence of the cardinal features of ADHD, which are hyperactivity, inattention, and impulsivity (for a review see ref. 23).In addition to regulation of DARPP-32, CK1 is likely to influence other aspects of neuronal function. The consensus sequence for CK1-dependent phosphorylation is well established (24, 25). However, the frequent requirement for a phospho-Ser or phosphoThr residue close to the site actually phosphorylated by CK1 makes it challenging to predict if a given protein will be phosphorylated by CK1. Moreover, existing CK1 inhibitors are not brain permeable. To circumvent these caveats, we chose to investigate the physiological importa...

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Section: Discussionmentioning

confidence: 99%

Forebrain overexpression of CK1δ leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD

Zhou

Rebholz²,

Brocia³

et al. 2010

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

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“…Newborn pups (postnatal day 0) were genotyped by PCR and then killed to prepare hippocampal neurons, as described by Gitler et al (2004). Microisland cultures of hippocampal neurons were prepared as described previously (Bekkers and Stevens, 1991;Feng et al, 2002), with the addition of glia feeder cells to support neuronal survival. Neurons were allowed to mature for 9 -13 d before being used for electrophysiological recordings.…”

Section: Methodsmentioning

confidence: 99%

Synaptotagmin I Synchronizes Transmitter Release in Mouse Hippocampal Neurons

2004

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We have asked whether loss of the Ca 2ϩ sensor protein synaptotagmin I influences the total amount of neurotransmitter released after a presynaptic action potential. Hippocampal neurons from synaptotagmin I knock-out mice had a greatly reduced fast synchronous component of glutamate release, as reported previously. However, the amount of glutamate released during the slow asynchronous component increased in these knock-out neurons. As a result of these changes in the kinetics of release, there was no significant difference between wild-type and knock-out neurons in the total amount of transmitter released within 400 msec after a presynaptic stimulus. Fluorescence imaging experiments demonstrated that wild-type and knock-out neurons take up and release similar amounts of FM dye after depolarization, indicating normal amounts of synaptic vesicle trafficking in the knock-out neurons. These results indicate that synaptotagmin I knock-out neurons are fully capable of releasing neurotransmitter, with the increased slow component of release serving to compensate for loss of the fast component. Thus, synaptotagmin I synchronizes the rapid release of neurotransmitters after Ca 2ϩ entry into presynaptic terminals and also appears to suppress the slower, asynchronous form of transmitter release.

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“…Glutamate and GABA presynaptic terminals also differ in their adaptive response to strong depolarization (Moulder et al, 2004). In other examples, different isoforms of vesicle and active zone proteins govern vesicle availability at glutamate and GABA synapses (Feng et al, 2002;Varoqueaux et al, 2002;Gitler et al, 2004). The subtype(s) of Ca 2ϩ channel driving release can differ between glutamate and GABA synapses, with most glutamate release controlled by a combination of P/Q-and N-type calcium channels (Luebke et al, 1993;Reid et al, 1997;Wu and Borst, 1999;Cao et al, 2004) and many GABA synapses governed by a single class of Ca 2ϩ channel (Poncer et al, 1997;Brager et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Vesicle Pool Heterogeneity at Hippocampal Glutamate and GABA Synapses

Moulder

Jiang²,

Taylor³

et al. 2007

J. Neurosci.

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Glutamate and GABA are the major fast excitatory and inhibitory neurotransmitters, respectively, in the CNS. Although glutamate and GABA have clearly distinct postsynaptic actions, we are just beginning to appreciate that presynaptic differences between glutamatergic and GABAergic neurons may contribute to distinct functions of these transmitter systems. We therefore probed possible differences between the functional synaptic vesicle populations of glutamatergic and GABAergic neurons. We examined superecliptic synaptopHluorin (SpH) fluorescence during 20 Hz electrical stimulation in transfected hippocampal neurons and identified the phenotype of SpH-fluorescent synapses with post hoc immunostaining. With 200 stimuli (10 s), individual glutamate synapses displayed considerably more variability in peak SpH fluorescence than GABA synapses, without a strong difference in the mean SpH fluorescence increase. This spatial heterogeneity could not be accounted for by differences in endocytosis, which was nearly constant over these short time periods across glutamate and GABA synapses. Instead, variability in vesicle exocytosis correlated with variability in total vesicle staining and in measures of the total recycling pool size. Differences were also evident using FM1-43 [N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide] uptake. These data support the idea that the population of glutamate synapses exhibits more heterogeneity in release properties than the population of GABA synapses, possibly correlated with glutamatergic synaptic malleability.

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Regulation of Neurotransmitter Release by Synapsin III

Cited by 142 publications

References 39 publications

Forebrain overexpression of CK1δ leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD

Forebrain overexpression of CK1δ leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD

Synaptotagmin I Synchronizes Transmitter Release in Mouse Hippocampal Neurons

Vesicle Pool Heterogeneity at Hippocampal Glutamate and GABA Synapses

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