Biomedical subjects

Reed C Carroll

Publications and source records attributed to Reed C Carroll.

5 recordsLinked to original sources

PubMed2006

Activity bidirectionally regulates AMPA receptor mRNA abundance in dendrites of hippocampal neurons.

Activity-dependent regulation of synaptic AMPA receptor (AMPAR) number is critical to NMDA receptor (NMDAR)-dependent synaptic plasticity. Using quantitative high-resolution in situ hybridization, we show that mRNAs encoding the AMPA-type glutamate receptor subunits (GluRs) 1 and 2 are localized to dendrites of hippocampal neurons and are regulated by paradigms that alter synaptic efficacy. A substantial fraction of synaptic sites contain AMPAR mRNA, consistent with strategic positioning and availability for "on-site" protein synthesis. NMDAR activation depletes dendritic levels of AMPAR mRNAs. The decrease in mRNA occurs via rise in intracellular Ca2+, activation of extracellular signal-regulated kinase/mitogen-activated protein kinase signaling, and transcriptional arrest at the level of the nucleus. The decrease in mRNA is accompanied by a long-lasting reduction in synaptic AMPAR number, consistent with reduced synaptic efficacy. In contrast, group I metabotropic GluR signaling promotes microtubule-based trafficking of existing AMPAR mRNAs from the soma to dendrites. Bidirectional regulation of dendritic mRNA abundance represents a potentially powerful means to effect long-lasting changes in synaptic strength.

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PubMed2006

State-dependent AMPA receptor trafficking in the mammalian retina.

The rapid cycling of AMPA receptors (AMPARs) at the membrane maintains synaptic transmission at a number of CNS synapses and may play a role in several forms of synaptic plasticity. It is unclear, however, how prevalent the trafficking of AMPARs is in the CNS, particularly at synapses not known to exhibit activity-dependent plasticity. Because trafficking is regulated by basal synaptic activity, a question also remains as to how receptor trafficking is modulated at synapses subject to different patterns of synaptic activation. We have investigated whether trafficking of AMPARs occurs in retinal neurons, which are subject to tonic glutamate release. We find two distinct states of AMPAR trafficking in ON ganglion cells. Light adaptation serves to stabilize AMPARs in a noncycling mode. However, dark adaptation for as little as 8 h triggers a switch to a second state of trafficking characterized by rapid cycling. We provide evidence that the activation of AMPARs is critical for switching between cycling and noncycling states. The induction of cycling further appears to be modulated by changes in the function of glutamate receptor 2/3-interacting proteins. Our results suggest that there is a strong link between synaptic activity and AMPAR trafficking in retinal neurons. These results further suggest the existence of a previously unknown form of activity-dependent plasticity in the retina that may be regulated in the course of a normal light/dark cycle.

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PubMed2006

Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses.

Genetic deficiency of the mRNA binding protein FMRP results in the most common inherited form of mental retardation, Fragile X syndrome. We investigated the localization and function of FMRP during development of hippocampal neurons in culture. FMRP was distributed within granules that extended into developing axons and growth cones, detectable at distances over 300 microm from the cell body. In mature cultures, FMRP granules were present in both axons and dendrites, with pockets of higher concentrations appearing intermittently, along distal axon segments and near synapses. MAP1b mRNA, a known FMRP target, was also localized to axon growth cones. Morphometric analysis of growth cones from the FMR1 KO revealed both excess filopodia and reduced motility. At later stages during synapse formation, FMR1 KO neurons exhibited excessive filopodia and long spines along dendrites, yet there was a marked decrease in the density of spine-like protrusions juxtaposed to presynaptic terminals. In contrast, there was no difference in the density of shaft synapses between FMR1 KO and WT. Brief depolarization of WT neurons resulted in increased numbers of filopodia and spine synapses, whereas no additional morphologic changes were observable in dendrites of FMR1 KO neurons that already had increased density of filopodia-spines. These findings suggest that alterations in the regulation of axonal growth and innervation in FMR1 KO neurons may contribute to the dendritic and spine pathology in Fragile X syndrome. This work has broader implications for understanding the role of mRNA binding proteins in developmental and protein-synthesis-dependent plasticity.

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PubMed2004

Metabotropic glutamate receptor activation regulates fragile x mental retardation protein and FMR1 mRNA localization differentially in dendrites and at synapses.

Fragile X syndrome is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP), which may play a role in activity-regulated localization and translation of mRNA in dendrites and at synapses. We investigated whether neuronal activity and glutamatergic signals regulate trafficking of FMRP and its encoding Fmr1 mRNA into dendrites or at synapses. Using high-resolution fluorescence and digital imaging microscopy in cultured hippocampal neurons, FMRP and Fmr1 mRNA were localized in granules throughout dendrites and within spines. KCl depolarization rapidly increased FMRP and Fmr1 mRNA levels in dendrites. Metabotropic glutamate receptor (mGluR) activation, in particular mGluR5 activation, was necessary for localization of FMRP into dendrites. Blockade of either PKC or internal calcium prevented mGluR-dependent localization of both FMRP and Fmr1 mRNA in dendrites. The activity-dependent localization of FMRP was not dependent on protein synthesis. Fluorescence recovery after photobleaching analysis of live neurons transfected with enhanced green fluorescent protein-FMRP revealed increased granule trafficking in response to KCl depolarization. In contrast to its dendritic localization, mGluR activation diminished FMRP, but not Fmr1 mRNA, localization at synapses. These results demonstrate regulation of FMRP and Fmr1 mRNA trafficking in dendrites and synapses in response to specific glutamatergic signals.

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PubMed2002

NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity.

Dynamic regulation of synaptic efficacy is thought to play a crucial role in formation of neuronal connections and in experience-dependent modification of neural circuitry. The molecular and cellular mechanisms by which synaptic changes are triggered and expressed are the focus of intense interest. This articles reviews recent evidence that NMDA receptors undergo dynamically regulated targeting and trafficking, and that the physical transport of NMDA receptors in and out of the synaptic membrane contributes to several forms of long-lasting synaptic plasticity. The identification of targeting and internalization sequences in NMDA-receptor subunits has begun the unraveling of some mechanisms that underlie activity-dependent redistribution of NMDA receptors. Given that NMDA receptors are widely expressed throughout the CNS, regulation of NMDA-receptor trafficking provides a potentially important way to modulate efficacy of synaptic transmission.

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