scholarly journals Rem2 regulates distinct homeostatic mechanisms in visual circuit plasticity

2017 ◽  
Author(s):  
Anna R. Moore ◽  
Sarah E. Richards ◽  
Katelyn Kenny ◽  
Leandro de Oliveira Royer ◽  
Urann Chan ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neural Circuit ◽  
Ocular Dominance ◽  
Scaling Up ◽  
Homeostatic Plasticity ◽  
Intrinsic Excitability ◽  
Neuronal Membrane ◽  
List Type ◽  
Ocular Dominance Plasticity

SUMMARYActivity-regulated genes sculpt neural circuits in response to sensory experience. These calcium-sensitive genes generally fall into two categories: transcription factors and proteins that function at synapses. Yet little is known about activity-regulated, cytosolic proteins that transduce signals between the neuronal membrane and the nucleus. Using the visual system as a model, we investigated the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in vivo. We demonstrate that Rem2-/- mice fail to exhibit normal ocular dominance plasticity during the critical period. At the circuit level, cortical layer 2/3 neurons in Rem2-/- mice show deficits in both postsynaptic scaling up of excitatory synapses and misregulation of intrinsic excitability. Further, we reveal that Rem2 plays a novel, cell-autonomous role in regulating neuronal intrinsic excitability. Thus, Rem2 is a critical regulator of neural circuit function and distinct homeostatic plasticity mechanisms in vivo.HIGHLIGHTSRem2 is required in excitatory cortical neurons for normal ocular dominance plasticityRem2 regulates postsynaptic homoeostatic synaptic scaling upRem2 alters the intrinsic excitability of neurons in a cell-autonomous manner

scholarly journals Homeostatic plasticity mechanisms in mouse V1

2017 ◽  
Vol 372 (1715) ◽  
pp. 20160504 ◽  
Author(s):  
Megumi Kaneko ◽  
Michael P. Stryker
Keyword(s):  
Visual Cortex ◽  
Primary Visual Cortex ◽  
Neuronal Activity ◽  
Dynamic Range ◽  
Ocular Dominance ◽  
Homeostatic Plasticity ◽  
Ocular Dominance Plasticity ◽  
The Brain

Mechanisms thought of as homeostatic must exist to maintain neuronal activity in the brain within the dynamic range in which neurons can signal. Several distinct mechanisms have been demonstrated experimentally. Three mechanisms that act to restore levels of activity in the primary visual cortex of mice after occlusion and restoration of vision in one eye, which give rise to the phenomenon of ocular dominance plasticity, are discussed. The existence of different mechanisms raises the issue of how these mechanisms operate together to converge on the same set points of activity. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’.

scholarly journals Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Anna R Moore ◽  
Sarah E Richards ◽  
Katelyn Kenny ◽  
Leandro Royer ◽  
Urann Chan ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Ocular Dominance ◽  
Sensory Experience ◽  
Cellular Level ◽  
Synaptic Function ◽  
Intrinsic Excitability ◽  
Spontaneous Firing ◽  
Circuit Function

Sensory experience plays an important role in shaping neural circuitry by affecting the synaptic connectivity and intrinsic properties of individual neurons. Identifying the molecular players responsible for converting external stimuli into altered neuronal output remains a crucial step in understanding experience-dependent plasticity and circuit function. Here, we investigate the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in visual circuit plasticity. We demonstrate that Rem2-/- mice fail to exhibit normal ocular dominance plasticity during the critical period. At the cellular level, our data establish a cell-autonomous role for Rem2 in regulating intrinsic excitability of layer 2/3 pyramidal neurons, prior to changes in synaptic function. Consistent with these findings, both in vitro and in vivo recordings reveal increased spontaneous firing rates in the absence of Rem2. Taken together, our data demonstrate that Rem2 is a key molecule that regulates neuronal excitability and circuit function in the context of changing sensory experience.

scholarly journals Metabotropic glutamate receptor signaling is required for NMDA receptor-dependent ocular dominance plasticity and LTD in visual cortex

2015 ◽  
Vol 112 (41) ◽  
pp. 12852-12857 ◽  
Author(s):  
Michael S. Sidorov ◽  
Eitan S. Kaplan ◽  
Emily K. Osterweil ◽  
Lothar Lindemann ◽  
Mark F. Bear
Keyword(s):  
Visual Cortex ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Ocular Dominance ◽  
Monocular Deprivation ◽  
Excitatory Synapses ◽  
Ocular Dominance Plasticity ◽  
Metabotropic Glutamate

A feature of early postnatal neocortical development is a transient peak in signaling via metabotropic glutamate receptor 5 (mGluR5). In visual cortex, this change coincides with increased sensitivity of excitatory synapses to monocular deprivation (MD). However, loss of visual responsiveness after MD occurs via mechanisms revealed by the study of long-term depression (LTD) of synaptic transmission, which in layer 4 is induced by acute activation of NMDA receptors (NMDARs) rather than mGluR5. Here we report that chronic postnatal down-regulation of mGluR5 signaling produces coordinated impairments in both NMDAR-dependent LTD in vitro and ocular dominance plasticity in vivo. The data suggest that ongoing mGluR5 signaling during a critical period of postnatal development establishes the biochemical conditions that are permissive for activity-dependent sculpting of excitatory synapses via the mechanism of NMDAR-dependent LTD.

scholarly journals Progressive maturation of silent synapses governs the duration of a critical period

2015 ◽  
Vol 112 (24) ◽  
pp. E3131-E3140 ◽  
Author(s):  
Xiaojie Huang ◽  
Sophia K. Stodieck ◽  
Bianka Goetze ◽  
Lei Cui ◽  
Man Ho Wong ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Critical Period ◽  
Neural Circuit ◽  
Ocular Dominance ◽  
Critical Periods ◽  
Ocular Dominance Plasticity ◽  
Silent Synapses ◽  
Synapse Maturation ◽  
Silent Synapse ◽  
Visual Cortical

During critical periods, all cortical neural circuits are refined to optimize their functional properties. The prevailing notion is that the balance between excitation and inhibition determines the onset and closure of critical periods. In contrast, we show that maturation of silent glutamatergic synapses onto principal neurons was sufficient to govern the duration of the critical period for ocular dominance plasticity in the visual cortex of mice. Specifically, postsynaptic density protein-95 (PSD-95) was absolutely required for experience-dependent maturation of silent synapses, and its absence before the onset of critical periods resulted in lifelong juvenile ocular dominance plasticity. Loss of PSD-95 in the visual cortex after the closure of the critical period reinstated silent synapses, resulting in reopening of juvenile-like ocular dominance plasticity. Additionally, silent synapse-based ocular dominance plasticity was largely independent of the inhibitory tone, whose developmental maturation was independent of PSD-95. Moreover, glutamatergic synaptic transmission onto parvalbumin-positive interneurons was unaltered in PSD-95 KO mice. These findings reveal not only that PSD-95–dependent silent synapse maturation in visual cortical principal neurons terminates the critical period for ocular dominance plasticity but also indicate that, in general, once silent synapses are consolidated in any neural circuit, initial experience-dependent functional optimization and critical periods end.

scholarly journals BDNF Regulates the Intrinsic Excitability of Cortical Neurons

1999 ◽  
Vol 6 (3) ◽  
pp. 284-291
Author(s):  
Niraj S. Desai ◽  
Lana C. Rutherford ◽  
Gina G. Turrigiano
Keyword(s):  
Cortical Neurons ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Homeostatic Plasticity ◽  
Intrinsic Excitability ◽  
Intrinsic Properties ◽  
General Role ◽  
Outward Currents ◽  
Visual Cortical ◽  
Activity Dependent

Neocortical pyramidal neurons respond to prolonged activity blockade by modulating their balance of inward and outward currents to become more sensitive to synaptic input, possibly as a means of homeostatically regulating firing rates during periods of intense change in synapse number or strength. Here we show that this activity-dependent regulation of intrinsic excitability depends on the neurotrophin brain-derived neurotrophic factor (BDNF). In experiments on rat visual cortical cultures, we found that exogenous BDNF prevented, and a TrkB–IgG fusion protein reproduced, the change in pyramidal neuron excitability produced by activity blockade. Most of these effects were also observed in bipolar interneurons, indicating a very general role for BDNF in regulating neuronal excitability. Moreover, earlier work has demonstrated that BDNF mediates a different kind of homeostatic plasticity present in these same cultures: scaling of the quantal amplitude of AMPA-mediated synaptic inputs up or down as a function of activity. Taken together, these results suggest that BDNF may be the signal controlling a coordinated regulation of synaptic and intrinsic properties aimed at allowing cortical networks to adapt to long-lasting changes in activity.

scholarly journals Genomic stability of Self-inactivating Rabies

2020 ◽  
Author(s):  
Ernesto Ciabatti ◽  
Ana González-Rueda ◽  
Daniel de Malmazet ◽  
Hassal Lee ◽  
Fabio Morgese ◽  
...  
Keyword(s):  
Cell Lines ◽  
Neural Circuit ◽  
Genetic Manipulation ◽  
Regulatory Element ◽  
Genomic Stability ◽  
List Type ◽  
Tev Protease ◽  
Production Cell

AbstractTranssynaptic viral vectors provide means to gain genetic access to neurons based on synaptic connectivity and are essential tools for the dissection of neural circuit function. Among them, the retrograde monosynaptic ΔG-Rabies has been widely used in neuroscience research. A recently developed engineered version of the ΔG-Rabies, the non-toxic self-inactivating (SiR) virus, represents the first tool for open-ended genetic manipulation of neural circuits. However, the high mutational rate of the rabies virus poses a risk that mutations targeting the key genetic regulatory element in the SiR genome could emerge and revert it to a canonical ΔG-Rabies. Such revertant mutations have recently been identified in a SiR batch. To address the origin, incidence and relevance of these mutations, we investigated the genomic stability of SiR in vitro and in vivo. We found that “revertant” mutations are rare and accumulate only when SiR is extensively amplified in vitro, particularly in suboptimal production cell lines that have insufficient levels of TEV protease activity. Moreover, we confirmed that SiR-CRE, unlike canonical ΔG-Rab-CRE or revertant-SiR-CRE, is non-toxic and that revertant mutations do not emerge in vivo during long-term experiments.HighlightsRevertant mutations are rare and do not accumulate when SiR is produced in high-TEVp expressing production cell linesSiR is non-toxic in vivoRevertant SiR mutations do not accumulate during in vivo experiments

scholarly journals Loss of Depalmitoylation Exaggerates Synaptic Upscaling and Leads to Neuroinflammation in a Lysosomal Storage Disease

2021 ◽  
Author(s):  
Kevin P Koster ◽  
Eden Flores-Barrera ◽  
Emilce Artur de la Villarmois ◽  
Thu T.A. Nguyen ◽  
Amanda Niqula ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Protein Trafficking ◽  
Cortical Neurons ◽  
Microglial Activation ◽  
Storage Disease ◽  
Homeostatic Plasticity ◽  
Synaptic Proteins ◽  
Lysosomal Storage ◽  
Palmitoyl Protein Thioesterase

Palmitoylation and depalmitoylation are the dichotomic processes of lipid modification regulating protein trafficking, recycling, and degradation, thereby controlling proteostasis. Despite our understanding of palmitoylation, depalmitoylation is far less studied. Here, we study a lysosomal depalmitoylating enzyme, palmitoyl-protein thioesterase 1 (PPT1), associated with the devastating neurodegenerative condition CLN1 disease and show that dark-rearing Ppt1-/- mice, which induces synaptic upscaling in vivo, worsen the symptoms. In Ppt1-/- cortical neurons, upscaling induction triggers exaggerated responses of synaptic calcium-permeable AMPA receptors composed of palmitoylated GluA1 subunits. Consequently, Ppt1-/- visual cortex exhibits hypersynchrony in vivo. Remarkably, we also find an overload of palmitoylated A-kinase anchor protein 5 (Akap5) in Ppt1-/- mouse brains, leading to microglial activation through NFAT. These findings indicate Ppt1 acts as a gatekeeper of homeostatic plasticity by regulating the proteostasis of palmitoylated synaptic proteins. Moreover, our results suggest that perturbed depalmitoylation results in neuroinflammation, which is common to neurodegenerative diseases.

scholarly journals Can ocular dominance plasticity provide a general index to visual plasticity to personalize treatment in amblyopia?

2020 ◽  
Author(s):  
Chunwen Tao ◽  
Zhifen He ◽  
Yiya Chen ◽  
Jiawei Zhou ◽  
Robert F. Hess
Keyword(s):  
Visual Acuity ◽  
Cortical Plasticity ◽  
Ocular Dominance ◽  
Monocular Deprivation ◽  
Homeostatic Plasticity ◽  
Ocular Dominance Plasticity ◽  
Anisometropic Amblyopia ◽  
Occlusion Therapy ◽  
General Index ◽  
Before And After

AbstractPurposeRecently, Lunghi et al showed that amblyopic eye’s visual acuity per se after 2 months of occlusion therapy could be predicted by a homeostatic plasticity, i.e., the temporary shift of ocular dominance observed after a 2-hour monocular deprivation, in children with anisometropic amblyopia(Lunghi et al., 2016). In this study, we assess whether the visual acuity improvement of the amblyopic eye measured after 2 months of occlusion therapy could be predicted by this plasticity.MethodsSeven children (6.86 ± 1.46 years old; SD) with anisometropic amblyopia participated in this study. All patients were newly diagnosed and had no treatment history before participating in our study. They had finished 2 months of refractive adaptation and then received a 4-hour daily fellow eye patching therapy with an opaque patch for a 2-month period. Best-corrected visual acuity of the amblyopic eye was measured before and after the patching therapy. The homeostatic plasticity was assessed by measuring the temporary shift of ocular dominance observed after 2 hours of occlusion for the amblyopic eye before the treatment started. A binocular phase combination paradigm was used for this test.ResultsWe found that there was no significant correlation between the temporary shift of ocular dominance observed after 2 hours of occlusion for the amblyopic eye before the treatment started and the visual acuity gain obtained by the amblyopic eye from 2-month of classical patching therapy. This result involving the short-term patching of the amblyopic eye is consistent with a reanalysis of Lunghi et al’ s data.ConclusionsOcular dominance plasticity does not provide an index of cortical plasticity in the general sense such that it could be used to predict acuity outcomes from longer term classical patching.

scholarly journals Kv1.1 contributes to a rapid homeostatic plasticity of intrinsic excitability in CA1 pyramidal neurons in vivo

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Peter James Morgan ◽  
Romain Bourboulou ◽  
Caroline Filippi ◽  
Julie Koenig-Gambini ◽  
Jérôme Epsztein
Keyword(s):  
Pyramidal Neurons ◽  
Place Cells ◽  
Homeostatic Plasticity ◽  
Intrinsic Excitability ◽  
Memory Interference ◽  
Ca1 Pyramidal Neurons ◽  
Whole Cell Patch Clamp ◽  
Activity Dependent

In area CA1 of the hippocampus, the selection of place cells to represent a new environment is biased towards neurons with higher excitability. However, different environments are represented by orthogonal cell ensembles, suggesting that regulatory mechanisms exist. Activity-dependent plasticity of intrinsic excitability, as observed in vitro, is an attractive candidate. Here, using whole-cell patch-clamp recordings of CA1 pyramidal neurons in anesthetized rats, we have examined how inducing theta-bursts of action potentials affects their intrinsic excitability over time. We observed a long-lasting, homeostatic depression of intrinsic excitability which commenced within minutes, and, in contrast to in vitro observations, was not mediated by dendritic Ih. Instead, it was attenuated by the Kv1.1 channel blocker dendrotoxin K, suggesting an axonal origin. Analysis of place cells’ out-of-field firing in mice navigating in virtual reality further revealed an experience-dependent reduction consistent with decreased excitability. We propose that this mechanism could reduce memory interference.

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