Glutamate Receptor Dynamics in Dendritic Microdomains

Newpher, Thomas M.; Ehlers, Michael

doi:10.1016/j.neuron.2008.04.030

Cited by 323 publications

(291 citation statements)

References 309 publications

(516 reference statements)

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“…These perisynaptic AMPARs can be removed by moderate synaptic activity (10) and this removal prevents the full expression of LTP and reverses spine expansion (6, 10). It has been suggested that perisynaptic AMPARs could play a critical role in regulating the persistence of LTP and spine expansion (10,12). This notion is consistent with the observation that stabilization of spine expansion requires synaptic incorporation of new AMPARs (6, 13).…”

supporting

confidence: 77%

Perisynaptic GluR2-lacking AMPA receptors control the reversibility of synaptic and spines modifications

Yang

Wang

Zhou

2010

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

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How persistent synaptic and spine modification is achieved is essential to our understanding of developmental refinement of neural circuitry and formation of memory. Within a short period after their induction, both types of modifications can either be stabilized or reversed, but how this reversibility is controlled is largely unknown. We have shown previously that AMPA receptors (AMPARs) are delivered to perisynaptic regions after the induction of long-term potentiation (LTP) but are absent from perisynaptic regions after the full expression of LTP. Here, we report that perisynaptic AMPARs are GluR2-lacking and they translocate to synapses in a protein kinase C (PKC)-dependent manner. Once entering synapses, these AMPARs quickly switch to GluR2-containing in an activity-dependent manner. Absence of postinduction activity or blocking interactions between GluR2 and NSF, or GluR2 and GRIP/ PICK1 results in LTP mediated by GluR2-lacking AMPARs. However, these synaptic GluR2-lacking AMPARs are not sufficient to allow reversibility of LTP. On the other hand, postsynaptic inhibition of PKC activity holds AMPARs at perisynaptic regions. As long as perisynaptic AMPARs are present, both LTP and spine expansion remain labile: they can be reverted to the baseline state together with removal of perisynaptic AMPARs, or they can enter a stabilized state of persistent increase together with synaptic incorporation of perisynaptic AMPARs. Thus, perisynaptic GluR2-lacking AMPARs play a critical role in controlling the reversibility of both synaptic and spine modifications.dendritic spine | long-term potentiation | two-photon imaging P ersistent functional and structural changes in synaptic connections are generally believed to underlie long-lasting modifications in neuronal networks, such as developmental refinement of neural circuitry and memory formation in the adult (1-3). One widely studied form of such long-lasting changes is long-term potentiation (LTP), which is accompanied by long-lasting expansion of dendritic spines (2-4). Within a short time window after LTP induction, both types of modifications can be reversed (5, 6). What controls the labile period of these modifications is of great importance to our understanding of the consolidation of synaptic and spine modifications.Modification of existing synaptic AMPA receptors (AMPARs) and/or addition of new AMPARs to synapses appear to underlie the expression of LTP. Evidence supports a model that newly added AMPARs first appear at extrasynaptic/perisynaptic regions and are subsequently incorporated into synapses (7-11). These perisynaptic AMPARs can be removed by moderate synaptic activity (10) and this removal prevents the full expression of LTP and reverses spine expansion (6, 10). It has been suggested that perisynaptic AMPARs could play a critical role in regulating the persistence of LTP and spine expansion (10,12). This notion is consistent with the observation that stabilization of spine expansion requires synaptic incorporation of new AMPARs (6, 13). A few studies ...

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supporting

confidence: 77%

Perisynaptic GluR2-lacking AMPA receptors control the reversibility of synaptic and spines modifications

Yang

Wang

Zhou

2010

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

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“…There is now a large body of experimental evidence that the fast trafficking of AMPA receptors into and out of spines is a major contributor to activity-dependent, long-lasting changes in synaptic strength (Bredt and Nicoll, 2003;Collinridge et al, 2004;Henley et al, 2011;Shepherd and Huganir, 2007). Single-particle tracking experiments suggest that surface AMPA receptors diffuse freely within the dendritic membrane until they enter a spine, where they are temporarily confined by the geometry of the spine and through interactions with scaffolding proteins and cytoskeletal elements (Choquet and Triller, 2003;Ehlers et al, 2007;Gerrow and Triller, 2010;Groc et al, 2004;Newpher and Ehlers, 2008;Triller and Choquet, 2005). A surface receptor may also be internalized via endocytosis and stored within an intracellular pool, where it is either recycled to the surface via exocytosis or degraded (Ehlers, 2000), see Fig.…”

Section: Diffusion Along Spiny Dendritesmentioning

confidence: 99%

“…The challenges of intracellular transport are particularly acute for brain cells (neurons), which are amongst the largest and most complex cells in biology, in particular, with regards to the efficient trafficking of newly synthesized proteins from the cell body or soma to distant locations on the axon or dendrites. In healthy cells, the regulation of protein trafficking within a neuron provides an important mechanism for modifying the strength of synaptic connections between neurons (Bredt and Nicoll, 2003;Choquet and Triller, 2003;Newpher and Ehlers, 2008;Triller and Choquet, 2005), and synaptic plasticity is generally believed to be the cellular substrate of learning and memory. On the other hand, various types of dysfunction in protein trafficking appear to be a major contributory factor to a number of neurodegenerative diseases associated with memory loss including Alzheimers (de Vos et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Stochastic models of intracellular transport

2013

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The interior of a living cell is a crowded, heterogenuous, fluctuating environment. Hence, a major challenge in modeling intracellular transport is to analyze stochastic processes within complex environments. Broadly speaking, there are two basic mechanisms for intracellular transport: passive diffusion and motor-driven active transport. Diffusive transport can be formulated in terms of the motion of an over-damped Brownian particle. On the other hand, active transport requires chemical energy, usually in the form of ATP hydrolysis, and can be direction specific, allowing biomolecules to be transported long distances; this is particularly important in neurons due to their complex geometry. In this review we present a wide range of analytical methods and models of intracellular transport. In the case of diffusive transport, we consider narrow escape problems, diffusion to a small target, confined and single-file diffusion, homogenization theory, and fractional diffusion. In the case of active transport, we consider Brownian ratchets, random walk models, exclusion processes, random intermittent search processes, quasisteady-state reduction methods, and mean field approximations. Applications include receptor trafficking, axonal transport, membrane diffusion, nuclear transport, protein-DNA interactions, virus trafficking, and the self-organization of subcellular structures.

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“…We have characterized the alternative splicing changes in Gria2 and Gria4, which encode core subunits of AMPA-type glutamate receptors that are critical for glutamatergic excitatory synapses (39). Alternative splicing via mutually exclusive exons generates flip or flop isoforms affecting the ligand-binding domain, which imparts different pharmacologic and kinetic properties on currents evoked by L-glutamate or AMPA (40).…”

Section: Sma Primarily Affects Spinal Cord Mnsmentioning

confidence: 99%

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Zhang

Pinto

Wan

et al. 2013

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

161

140

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The motor neuron (MN) degenerative disease, spinal muscular atrophy (SMA) is caused by deficiency of SMN (survival motor neuron), a ubiquitous and indispensable protein essential for biogenesis of snRNPs, key components of pre-mRNA processing. However, SMA's hallmark MN pathology, including neuromuscular junction (NMJ) disruption and sensory-motor circuitry impairment, remains unexplained. Toward this end, we used deep RNA sequencing (RNA-seq) to determine if there are any transcriptome changes in MNs and surrounding spinal cord glial cells (white matter, WM) microdissected from SMN-deficient SMA mouse model at presymptomatic postnatal day 1 (P1), before detectable MN pathology (P4-P5). The RNA-seq results, previously unavailable for SMA at any stage, revealed cell-specific selective mRNA dysregulations (∼300 of 11,000 expressed genes in each, MN and WM), many of which are known to impair neurons. Remarkably, these dysregulations include complete skipping of agrin's Z exons, critical for NMJ maintenance, strong upregulation of synapse pruning-promoting complement factor C1q, and down-regulation of Etv1/ER81, a transcription factor required for establishing sensory-motor circuitry. We propose that dysregulation of such specific MN synaptogenesis genes, compounded by many additional transcriptome abnormalities in MNs and WM, link SMN deficiency to SMA's signature pathology.transcriptome perturbations | Z+ (neuronal) agrin | C1q complex S pinal muscular atrophy (SMA) is an autosomal recessive motor neuron (MN) degenerative disease and a leading genetic cause of infant mortality (1, 2). SMA is caused by deletions or point mutations in the survival of motor neurons 1 gene (SMN1) (3), exposing a splicing defect in a duplicated gene (SMN2), which produces predominantly exon 7-skipped mRNA (SMNΔ7) (4). This in turn creates a degron that destabilizes the SMNΔ7 protein, resulting in reduced SMN levels (SMN deficiency) (5). SMA pathology has been extensively characterized in patients as well as a widely used SMA mouse model (6). Major morphological and biochemical deficits have been found at neuromuscular junctions (NMJs) and sensory-motor synapses. NMJ defects are first detectable at postnatal day 5 (P5), including presynaptic defects of terminal arborization and intermediate neurofilament aggregation in MNs, poor postsynaptic organization of AChRs in muscle, as well as reduced synaptic vesicle density and release at the NMJ (7-9). Importantly, similar NMJ defects have been reported in type I (the most severe type) SMA human fetuses (10). SMA MNs have also been shown to be hyperexcitable and loss of proprioceptive synapses on the somata, and proximal dendrites of SMA MNs (MN deafferentation) occurs no later than P4 (11-13). These findings indicate that both peripheral (NMJs) and central (sensory-motor) synapses are affected in SMA mice at early stage of disease. Although SMA is clinically manifested primarily in MNs, recent studies have shown that other cell types and nonneuronal tissues are also involved (13,14,15). SMN,...

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Glutamate Receptor Dynamics in Dendritic Microdomains

Cited by 323 publications

References 309 publications

Perisynaptic GluR2-lacking AMPA receptors control the reversibility of synaptic and spines modifications

Perisynaptic GluR2-lacking AMPA receptors control the reversibility of synaptic and spines modifications

Stochastic models of intracellular transport

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

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