Circuit and Plasticity Defects in the Developing Somatosensory Cortex of<i>Fmr1</i>Knock-Out Mice

Bureau, Ingrid; Shepherd, Gordon M.; Svoboda, Karel

doi:10.1523/jneurosci.1076-08.2008

Cited by 183 publications

(215 citation statements)

References 80 publications

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“…However, only a few studies have used LSPS to study the development (Dalva and Katz, 1994;Bureau et al, 2004;Ashby and Isaac, 2011;Viswanathan et al, 2012) and plasticity (Jin et al, 2006(Jin et al, , 2011Bureau et al, 2008;Rosselet et al, 2011) of neocortical synaptic inputs. The majority of experiments have used LSPS on neurons held at near resting membrane potential to identify predominantly AMPARmediated afferent input.…”

Section: Discussionmentioning

confidence: 99%

A Role for Silent Synapses in the Development of the Pathway from Layer 2/3 to 5 Pyramidal Cells in the Neocortex

Anastasiades

Butt

2012

J. Neurosci.

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The integration of neurons within the developing cerebral cortex is a prolonged process dependent on a combination of molecular and physiological cues. To examine the latter we used laser scanning photostimulation (LSPS) of caged glutamate in conjunction with whole-cell patch-clamp electrophysiology to probe the integration of pyramidal cells in the sensorimotor regions of the mouse neocortex. In the days immediately after postnatal day 5 (P5) the origin of the LSPS-evoked AMPA receptor (AMPAR)-mediated synaptic inputs were diffuse and poorly defined with considerable variability between cells. Over the subsequent week this coalesced and shifted, primarily influenced by an increased contribution from layers 2/3 cells, which became a prominent motif of the afferent input onto layer 5 pyramidal cells regardless of cortical region. To further investigate this particular emergent translaminar connection, we alternated our mapping protocol between two holding potentials (Ϫ70 and ϩ40 mV) allowing us to detect exclusively NMDA receptor (NMDAR)-mediated inputs. This revealed distal MK-801-sensitive synaptic inputs that predict the formation of the mature, canonical layer 2/3 to 5 pathway. However, these were a transient feature and had been almost entirely converted to AMPAR synapses at a later age (P16). To examine the role of activity in the recruitment of early NMDAR synapses, we evoked brief periods (20 min) of rhythmic bursting. Short intense periods of activity could cause a prolonged augmentation of the total input onto pyramidal cells up until P12; a time point when the canonical circuit has been instated and synaptic integration shifts to a more consolidatory phase.

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Section: Discussionmentioning

confidence: 99%

A Role for Silent Synapses in the Development of the Pathway from Layer 2/3 to 5 Pyramidal Cells in the Neocortex

Anastasiades

Butt

2012

J. Neurosci.

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“…Consistently, Fmr1-knockout mice exhibit dendritic abnormalities (Kooy, 2003), associated with brain region-specific defects in activity-dependent critical periods (Cruz-Martin et al, 2010). Synaptically localized FMRP is upregulated by activity, and in turn modulates activity and controls activity-dependent processes including synapse elimination (Antar et al, 2004;Gabel et al, 2004;Pfeiffer and Huber, 2007;Bureau et al, 2008;Tessier and Broadie, 2008;Pfeiffer et al, 2010).…”

Section: Introductionmentioning

confidence: 92%

Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory

2015

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The activity-dependent refinement of neural circuit connectivity during critical periods of brain development is essential for optimized behavioral performance. We hypothesize that this mechanism is defective in fragile X syndrome (FXS), the leading heritable cause of intellectual disability and autism spectrum disorders. Here, we use optogenetic tools in the Drosophila FXS disease model to test activitydependent dendritogenesis in two extrinsic neurons of the mushroom body (MB) learning and memory brain center: (1) the input projection neuron (PN) innervating Kenyon cells (KCs) in the MB calyx microglomeruli and (2) the output MVP2 neuron innervated by KCs in the MB peduncle. Both input and output neuron classes exhibit distinctive activity-dependent critical period dendritic remodeling. MVP2 arbors expand in Drosophila mutants null for fragile X mental retardation 1 (dfmr1), as well as following channelrhodopsin-driven depolarization during critical period development, but are reduced by halorhodopsin-driven hyperpolarization. Optogenetic manipulation of PNs causes the opposite outcome -reduced dendritic arbors following channelrhodopsin depolarization and expanded arbors following halorhodopsin hyperpolarization during development. Importantly, activity-dependent dendritogenesis in both neuron classes absolutely requires dfmr1 during one developmental window. These results show that dfmr1 acts in a neuron type-specific activity-dependent manner for sculpting dendritic arbors during early-use, critical period development of learning and memory circuitry in the Drosophila brain.

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“…Gatto and Broadie (2009) reported abnormalities in circadian clock circuits in dfmr1 mutant Drosophila, which were due to aberrant synaptic architecture and could be rescued by temporally controlled overexpression of dFMRP. In Fmr1 KO mice, dysregulated neuronal connectivity in the barrel cortex (Bureau et al, 2008) leads to defective glutamatergic synapse maturation, delayed and aberrant formation of sensory maps, and altered synaptic plasticity during the critical period (Harlow et al, 2010). In general, loss of FMRP seems to lead to altered network synchrony and hyperexcitable neuronal networks (Chuang et al, 2005;Gibson et al, 2008).…”

Section: Altered Neuronal Network Formation In Fxsmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

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Circuit and Plasticity Defects in the Developing Somatosensory Cortex ofFmr1Knock-Out Mice

Cited by 183 publications

References 80 publications

A Role for Silent Synapses in the Development of the Pathway from Layer 2/3 to 5 Pyramidal Cells in the Neocortex

A Role for Silent Synapses in the Development of the Pathway from Layer 2/3 to 5 Pyramidal Cells in the Neocortex

Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

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