scholarly journals ADAR2 mediated Q/R editing of GluK2 regulates homeostatic plasticity of kainate receptors

2018 ◽  
Author(s):  
Sonam Gurung ◽  
Ashley J. Evans ◽  
Kevin A. Wilkinson ◽  
Jeremy M. Henley
Keyword(s):  
Neuronal Excitability ◽  
Surface Expression ◽  
Synaptic Activity ◽  
Homeostatic Plasticity ◽  
Kainate Receptors ◽  
Mrna Editing ◽  
Network Function ◽  
Pore Lining ◽  
Activity Dependent ◽  
The Brain

AbstractKainate receptors (KARs) are heteromeric glutamate-gated ion channels that regulate neuronal excitability and network function in the brain. Most KARs contain the subunit GluK2 and the precise properties of these GluK2-containing KARs are determined by additional factors including ADAR2-mediated mRNA editing of a single codon that changes a genomically encoded glutamine (Q) to arginine (R) in the pore-lining region of GluK2. ADAR2-dependent Q/R editing of GluK2 is dynamically regulated during homeostatic plasticity (scaling) elicited by suppression of synaptic activity with TTX. Here we show that TTX decreases levels of ADAR2 by enhancing its proteasomal degradation. This selectively reduces the numbers of GluK2 subunits that are edited and increases the surface expression of GluK2-containing KARs. Furthermore, we show that partial ADAR2 knockdown phenocopies and occludes TTX-induced scaling of KARs. These data indicate that activity-dependent regulation of ADAR2 proteostasis and GluK2 Q/R editing provides a mechanism for KAR homeostatic plasticity.

scholarly journals ADAR2-mediated Q/R editing of GluK2 regulates kainate receptor upscaling in response to suppression of synaptic activity

2018 ◽  
Author(s):  
Sonam Gurung ◽  
Ashley J. Evans ◽  
Kevin A. Wilkinson ◽  
Jeremy M. Henley
Keyword(s):  
Neuronal Excitability ◽  
Proteasomal Degradation ◽  
Surface Expression ◽  
Synaptic Activity ◽  
Kainate Receptors ◽  
Kainate Receptor ◽  
Mrna Editing ◽  
Network Function ◽  
Ampar Trafficking ◽  
Editing Enzyme

AbstractKainate receptors (KARs) regulate neuronal excitability and network function. Most KARs contain the subunit GluK2 and the properties of these receptors are determined in part by ADAR2-mediated mRNA editing of GluK2 that changes a genomically encoded glutamine (Q) to arginine (R). Suppression of synaptic activity reduces ADAR2-dependent Q/R editing of GluK2 with a consequential increase in GluK2-containing KAR surface expression. However, the mechanism underlying this reduction in GluK2 editing has not been addressed. Here we show that induction of KAR upscaling results in proteasomal degradation of ADAR2, which reduces GluK2 Q/R editing. Because KARs incorporating unedited GluK2(Q) assemble and exit the ER more efficiently this leads to an upscaling of KAR surface expression. Consistent with this, we demonstrate that partial ADAR2 knockdown phenocopies and occludes KAR upscaling. Moreover, we show that although the AMPAR subunit GluA2 also undergoes ADAR2-dependent Q/R editing, this process does not mediate AMPAR upscaling. These data demonstrate that activity-dependent regulation of ADAR2 proteostasis and GluK2 Q/R editing are key determinants of KAR, but not AMPAR, trafficking and upscaling.Summary statementSynaptic suppression promotes proteasomal degradation of the mRNA-editing enzyme ADAR2. Decreased ADAR2 levels reduce Q/R editing of the kainate receptor subunit GluK2 leading to enhanced surface expression and homeostatic upscaling.

scholarly journals Activity-dependent, homeostatic regulation of neurotransmitter release from auditory nerve fibers

2015 ◽  
Vol 112 (20) ◽  
pp. 6479-6484 ◽  
Author(s):  
Tenzin Ngodup ◽  
Jack A. Goetz ◽  
Brian C. McGuire ◽  
Wei Sun ◽  
Amanda M. Lauer ◽  
...  
Keyword(s):  
Auditory Nerve ◽  
Neurotransmitter Release ◽  
High Reliability ◽  
Downstream Processing ◽  
Nerve Fibers ◽  
Synaptic Activity ◽  
Quantal Size ◽  
Activity Dependent ◽  
The Brain ◽  
Homeostatic Response

Information processing in the brain requires reliable synaptic transmission. High reliability at specialized auditory nerve synapses in the cochlear nucleus results from many release sites (N), high probability of neurotransmitter release (Pr), and large quantal size (Q). However, high Pr also causes auditory nerve synapses to depress strongly when activated at normal rates for a prolonged period, which reduces fidelity. We studied how synapses are influenced by prolonged activity by exposing mice to constant, nondamaging noise and found that auditory nerve synapses changed to facilitating, reflecting low Pr. For mice returned to quiet, synapses recovered to normal depression, suggesting that these changes are a homeostatic response to activity. Two additional properties, Q and average excitatory postsynaptic current (EPSC) amplitude, were unaffected by noise rearing, suggesting that the number of release sites (N) must increase to compensate for decreased Pr. These changes in N and Pr were confirmed physiologically using the integration method. Furthermore, consistent with increased N, endbulbs in noise-reared animals had larger VGlut1-positive puncta, larger profiles in electron micrographs, and more release sites per profile. In current-clamp recordings, noise-reared BCs had greater spike fidelity even during high rates of synaptic activity. Thus, auditory nerve synapses regulate excitability through an activity-dependent, homeostatic mechanism, which could have major effects on all downstream processing. Our results also suggest that noise-exposed bushy cells would remain hyperexcitable for a period after returning to normal quiet conditions, which could have perceptual consequences.

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 Activity-dependent expression of reporter proteins at dendritic spines for synaptic activity mapping and optogenetic stimulation

2016 ◽  
Author(s):  
Francesco Gobbo ◽  
Laura Marchetti ◽  
Claudia Alia ◽  
Stefano Luin ◽  
Antonino Cattaneo
Keyword(s):  
Dendritic Spines ◽  
Cognitive Disorders ◽  
Synaptic Activity ◽  
Regulatory Sequences ◽  
Synaptic Connections ◽  
Optogenetic Stimulation ◽  
Reporter Proteins ◽  
Activity Dependent ◽  
The Brain ◽  
Spine Number

Increasing evidence points to the importance of dendritic spines in the formation and allocation of memories, and alterations of spine number and physiology are associated to memory and cognitive disorders. Synaptic connections and pathways constitute the physical substrate that conveys information in the brain, and different combinations of active synaptic connections are believed to be responsible for the encoding of specific memories. In addition, modifications of the activity of such subsets of synapses are believed to be crucial for memory establishment, but a way to directly test this hypothesis, by selectively controlling the activity of potentiated spines, is currently lagging behind. Therefore it would be important to develop methods to tag active synapses for mapping functionally active connections and to selectively stimulate or interfere with active synapses. Here we introduce an approach to express light-sensitive membrane channels at synapses in an activity-dependent way by means of RNA and protein regulatory sequences. This approach is based on the local expression of reporter proteins, including optogenetic probes, at activated synapses and will allow the mapping of previously active synapses and the re-activation of the neuron only at these sites. This will allow extending the investigation of memory processes beyond the current neuron tagging technologies, whose resolution is limited at the cellular scale. Thus, it will be possible to unveil and recall the synaptic engram out of the global set of synapses.

scholarly journals Astrocytic modulation of excitatory synaptic signaling in a mouse model of Rett syndrome

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Benjamin Rakela ◽  
Paul Brehm ◽  
Gail Mandel
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Synaptic Activity ◽  
Wild Type ◽  
Synaptic Signaling ◽  
Network Function ◽  
Mosaic Distribution ◽  
Mutant Cells ◽  
The Brain ◽  
Expression Status

Studies linking mutations in Methyl CpG Binding Protein 2 (MeCP2) to physiological defects in the neurological disease, Rett syndrome, have focused largely upon neuronal dysfunction despite MeCP2 ubiquitous expression. Here we explore roles for astrocytes in neuronal network function using cortical slice recordings. We find that astrocyte stimulation in wild-type mice increases excitatory synaptic activity that is absent in male mice lacking MeCP2 globally. To determine the cellular basis of the defect, we exploit a female mouse model for Rett syndrome that expresses wild-type MeCP2-GFP in a mosaic distribution throughout the brain, allowing us to test all combinations of wild-type and mutant cells. We find that the defect is dependent upon MeCP2 expression status in the astrocytes and not in the neurons. Our findings highlight a new role for astrocytes in regulation of excitatory synaptic signaling and in the neurological defects associated with Rett syndrome.

scholarly journals MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons

2019 ◽  
Vol 116 (12) ◽  
pp. 5727-5736 ◽  
Author(s):  
Mariline M. Silva ◽  
Beatriz Rodrigues ◽  
Joana Fernandes ◽  
Sandra D. Santos ◽  
Laura Carreto ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Surface Expression ◽  
Receptor Expression ◽  
Synaptic Activity ◽  
Synaptic Scaling ◽  
Posttranscriptional Control ◽  
Direct Target ◽  
Activity Dependent

Homeostatic synaptic scaling is a negative feedback response to fluctuations in synaptic strength induced by developmental or learning-related processes, which maintains neuronal activity stable. Although several components of the synaptic scaling apparatus have been characterized, the intrinsic regulatory mechanisms promoting scaling remain largely unknown. MicroRNAs may contribute to posttranscriptional control of mRNAs implicated in different stages of synaptic scaling, but their role in these mechanisms is still undervalued. Here, we report that chronic blockade of glutamate receptors of the AMPA and NMDA types in hippocampal neurons in culture induces changes in the neuronal mRNA and miRNA transcriptomes, leading to synaptic upscaling. Specifically, we show that synaptic activity blockade persistently down-regulates miR-186-5p. Moreover, we describe a conserved miR-186-5p-binding site within the 3′UTR of the mRNA encoding the AMPA receptor GluA2 subunit, and demonstrate that GluA2 is a direct target of miR-186-5p. Overexpression of miR-186 decreased GluA2 surface levels, increased synaptic expression of GluA2-lacking AMPA receptors, and blocked synaptic scaling, whereas inhibition of miR-186-5p increased GluA2 surface levels and the amplitude and frequency of AMPA receptor-mediated currents, and mimicked excitatory synaptic scaling induced by synaptic inactivity. Our findings elucidate an activity-dependent miRNA-mediated mechanism for regulation of AMPA receptor expression.

scholarly journals Differential requirement for NMDAR activity in SAP97β-mediated regulation of the number and strength of glutamatergic AMPAR-containing synapses

2014 ◽  
Vol 111 (3) ◽  
pp. 648-658 ◽  
Author(s):  
Mingna Liu ◽  
Laura D. Lewis ◽  
Rebecca Shi ◽  
Emery N. Brown ◽  
Weifeng Xu
Keyword(s):  
Molecular Diversity ◽  
Surface Expression ◽  
Dependent Manner ◽  
Molecular Replacement ◽  
Glutamatergic Synapses ◽  
Glutamatergic Synaptic Transmission ◽  
Molecular Substrates ◽  
Activity Dependent ◽  
The Brain ◽  
Synaptic Responses

PSD-95-like, disc-large (DLG) family membrane-associated guanylate kinase proteins (PSD/DLG-MAGUKs) are essential for regulating synaptic AMPA receptor (AMPAR) function and activity-dependent trafficking of AMPARs. Using a molecular replacement strategy to replace endogenous PSD-95 with SAP97β, we show that the prototypic β-isoform of the PSD-MAGUKs, SAP97β, has distinct NMDA receptor (NMDAR)-dependent roles in regulating basic properties of AMPAR-containing synapses. SAP97β enhances the number of AMPAR-containing synapses in an NMDAR-dependent manner, whereas its effect on the size of unitary synaptic response is not fully dependent on NMDAR activity. These effects contrast with those of PSD-95α, which increases both the number of AMPAR-containing synapses and the size of unitary synaptic responses, with or without NMDAR activity. Our results suggest that SAP97β regulates synaptic AMPAR content by increasing surface expression of GluA1-containing AMPARs, whereas PSD-95α enhances synaptic AMPAR content presumably by increasing the synaptic scaffold capacity for synaptic AMPARs. Our approach delineates discrete effects of different PSD-MAGUKs on principal properties of glutamatergic synaptic transmission. Our results suggest that the molecular diversity of PSD-MAGUKs can provide rich molecular substrates for differential regulation of glutamatergic synapses in the brain.

scholarly journals SUMO modification of cell surface Kv2.1 potassium channels regulates the activity of rat hippocampal neurons

2011 ◽  
Vol 137 (5) ◽  
pp. 441-454 ◽  
Author(s):  
Leigh D. Plant ◽  
Evan J. Dowdell ◽  
Irina S. Dementieva ◽  
Jeremy D. Marks ◽  
Steve A.N. Goldstein
Keyword(s):  
Potassium Channels ◽  
Cell Surface ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Voltage Gated ◽  
Sumo Modification ◽  
Maximal Activation ◽  
Sumo Pathway ◽  
Activity Dependent ◽  
The Brain

Voltage-gated Kv2.1 potassium channels are important in the brain for determining activity-dependent excitability. Small ubiquitin-like modifier proteins (SUMOs) regulate function through reversible, enzyme-mediated conjugation to target lysine(s). Here, sumoylation of Kv2.1 in hippocampal neurons is shown to regulate firing by shifting the half-maximal activation voltage (V1/2) of channels up to 35 mV. Native SUMO and Kv2.1 are shown to interact within and outside channel clusters at the neuronal surface. Studies of single, heterologously expressed Kv2.1 channels show that only K470 is sumoylated. The channels have four subunits, but no more than two non-adjacent subunits carry SUMO concurrently. SUMO on one site shifts V1/2 by 15 mV, whereas sumoylation of two sites produces a full response. Thus, the SUMO pathway regulates neuronal excitability via Kv2.1 in a direct and graded manner.

scholarly journals Modeling temperature- and Cav3 subtype-dependent alterations in T-type calcium channel mediated burst firing

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Fernando R. Fernandez ◽  
Mircea C. Iftinca ◽  
Gerald W. Zamponi ◽  
Ray W. Turner
Keyword(s):  
Calcium Channel ◽  
Neuronal Excitability ◽  
Neuronal Firing ◽  
Mammalian Brain ◽  
Peripheral Tissues ◽  
Window Current ◽  
Modeling Data ◽  
The Brain ◽  
Firing Neuron ◽  
Cav3 Channel

AbstractT-type calcium channels are important regulators of neuronal excitability. The mammalian brain expresses three T-type channel isoforms (Cav3.1, Cav3.2 and Cav3.3) with distinct biophysical properties that are critically regulated by temperature. Here, we test the effects of how temperature affects spike output in a reduced firing neuron model expressing specific Cav3 channel isoforms. The modeling data revealed only a minimal effect on baseline spontaneous firing near rest, but a dramatic increase in rebound burst discharge frequency for Cav3.1 compared to Cav3.2 or Cav3.3 due to differences in window current or activation/recovery time constants. The reduced response by Cav3.2 could optimize its activity where it is expressed in peripheral tissues more subject to temperature variations than Cav3.1 or Cav3.3 channels expressed prominently in the brain. These tests thus reveal that aspects of neuronal firing behavior are critically dependent on both temperature and T-type calcium channel subtype.

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