LTP) And Depression Research Articles

Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modeling

Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease, but the mechanisms of these deficits are unknown. Genomic association studies have implicated a large number of genes that regulate neuromodulation and plasticity, indicating that the plasticity deficits have a genetic origin. Here, we used biochemically detailed computational modeling of postsynaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD). We combined our model with data from postmortem RNA expression studies (CommonMind gene-expression datasets) to assess the consequences of altered expression of plasticity-regulating genes for the amplitude of LTP and LTD. Our results show that the expression alterations observed post mortem, especially those in the anterior cingulate cortex, lead to impaired protein kinase A (PKA)-pathway-mediated LTP in synapses containing GluR1 receptors. We validated these findings using a genotyped electroencephalogram (EEG) dataset where polygenic risk scores for synaptic and ion channel-encoding genes as well as modulation of visual evoked potentials were determined for 286 healthy controls. Our results provide a possible genetic mechanism for plasticity impairments in schizophrenia, which can lead to improved understanding and, ultimately, treatment of the disorder.

High-performance memristor for energy-efficient artificial optoelectronic synapse based on BiVO4 nanosheets

Artificial optoelectronic synapses have drawn extensive attention owing to their ability to combine the optical and electrical responses. Those photosensitive materials that has been reported in memristors have the potential to be adopted in such optoelectronic synapses. Herein, optoelectronic synapses can be achieved based on two-terminal memristors by using two-dimensional (2D) BiVO4 with monoclinic scheelite (m-BiVO4) structure as the memristive layer. The fabricated memristors exhibit bipolar resistive switching (RS) characteristics with stable retention and reliable endurance performance. Furthermore, both electrical and optical synaptic functions can be achieved based on the memristors, such as long-term potentiation (LTP) and depression (LTD) stimulated by the voltages pulses as well as short-term and long-term memory under the light stimulation. More importantly, owing to the LTP and LTD functions with high symmetry, linearity and good repeatability of the LTP/LTD cycles, the artificial neural network can be simulated to achieve image recognition with a high accuracy for handwritten digits. Moreover, both the electrical and optical synapses can be used to emulate the “learning-forgetting” behaviors of human brain. Remarkably, the energy consumption per synaptic event in the optical and electrical modes can be calculated, indicating potential applications in energy-efficient synaptic devices. The m-BiVO4 nanosheets not only demonstrate good non-volatile RS behaviors but also implement energy-efficient optoelectronic synaptic functions, providing a promising strategy for applications in future neuromorphic computing.

Unraveling the mysteries of dendritic spine dynamics: Five key principles shaping memory and cognition.

Recent research extends our understanding of brain processes beyond just action potentials and chemical transmissions within neural circuits, emphasizing the mechanical forces generated by excitatory synapses on dendritic spines to modulate presynaptic function. From in vivo and in vitro studies, we outline five central principles of synaptic mechanics in brain function: P1: Stability - Underpinning the integral relationship between the structure and function of the spine synapses. P2: Extrinsic dynamics - Highlighting synapse-selective structural plasticity which plays a crucial role in Hebbian associative learning, distinct from pathway-selective long-term potentiation (LTP) and depression (LTD). P3: Neuromodulation - Analyzing the role of G-protein-coupled receptors, particularly dopamine receptors, in time-sensitive modulation of associative learning frameworks such as Pavlovian classical conditioning and Thorndike's reinforcement learning (RL). P4: Instability - Addressing the intrinsic dynamics crucial to memory management during continual learning, spotlighting their role in "spine dysgenesis" associated with mental disorders. P5: Mechanics - Exploring how synaptic mechanics influence both sides of synapses to establish structural traces of short- and long-term memory, thereby aiding the integration of mental functions. We also delve into the historical background and foresee impending challenges.

Altering stimulus timing via fast rhythmic sensory stimulation induces STDP-like recall performance in human episodic memory

Episodic memory provides humans with the ability to mentally travel back to the past,1 where experiences typically involve associations between multimodal information. Forming a memory of the association is thought to be dependent on modification of synaptic connectivity.2,3 Animal studies suggest that the strength of synaptic modification depends on spike timing between pre- and post-synaptic neurons on the order of tens of milliseconds, which is termed "spike-timing-dependent plasticity" (STDP).4 Evidence found in human invitro studies suggests different temporal scales in long-term potentiation (LTP) and depression (LTD), compared with the critical time window of STDP in animals.5,6 In the healthy human brain, STDP-like effects have been shown in the motor cortex, visual perception, and face identity recognition.7,8,9,10,11,12,13 However, evidence in human episodic memory is lacking. We investigated this using rhythmic sensory stimulation to drive visual and auditory cortices at 37.5Hz with four phase offsets. Visual relative to auditory cued recall accuracy was significantly enhanced in the 90° condition when the visual stimulus led at the shortest delay (6.67ms). This pattern was reversed in the 270° condition when the auditory stimulus led at the shortest delay. Within cue modality, recall was enhanced when a stimulus of the corresponding modality led the shortest delay (6.67ms) compared with the longest delay (20ms). Our findings provide evidence for STDP in human episodic memory, which builds an important bridge from invitro studies in animals to human memory behavior.

W-doped In2O3 nanofiber optoelectronic neuromorphic transistors with synergistic synaptic plasticity

Neuromorphic devices that mimic the information processing function of biological synapses and neurons have attracted considerable attention due to their potential applications in brain-like perception and computing. In this paper, neuromorphic transistors with W-doped In2O3 nanofibers as the channel layers are fabricated and optoelectronic synergistic synaptic plasticity is also investigated. Such nanofiber transistors can be used to emulate some biological synaptic functions, including excitatory postsynaptic current (EPSC), long-term potentiation (LTP), and depression (LTD). Moreover, the synaptic plasticity of the nanofiber transistor can be synergistically modulated by light pulse and electrical pulse. At last, pulsed light learning and pulsed electrical forgetting behaviors were emulated in 5 × 5 nanofiber device array. Our results provide new insights into the development of nanofiber optoelectronic neuromorphic devices with synergistic synaptic plasticity.

Controlling diffusion dynamics with electrode engineering for stable and reliable resistive switching in AlN/Ag-based CBRAM

Due to high scalability, quick operating speed, wide dynamic on–off resistance range, and analog current switching, cation migration-based conductive bridge random access memory (CBRAM) has received much attention for a wide range of applications including data storage, logic gates, and neuromorphic circuits. However, Inadequate controllability of metal-ion injection and the creation of numerous filaments are the major issues for the switching stability. In this work, we investigated Ag/Ta/Ag stacked electrode structure to improve cycle-to-cycle and device-to-device switching uniformity by controlling the Ag-ion diffusion into the host material. The device shows stable dc endurance for 100 switching cycles without much degradation. The data retention behavior for 104 s is observed in the stacked electrode device at room temperature as well as an elevated temperature of 80 °C. The proposed device emulates biological synaptic functionality by demonstrating long-term potentiation(LTP) and depression (LTD) behavior for 10 epochs.

MGluR-dependent plasticity in rodent models of Alzheimer's disease.

Long-term potentiation (LTP) and depression (LTD) are currently the most comprehensive models of synaptic plasticity models to subserve learning and memory. In the CA1 region of the hippocampus LTP and LTD can be induced by the activation of either NMDA receptors or mGluR5 metabotropic glutamate receptors. Alterations in either form of synaptic plasticity, NMDAR-dependent or mGluR-dependent, are attractive candidates to contribute to learning deficits in conditions like Alzheimer's disease (AD) and aging. Research, however, has focused predominantly on NMDAR-dependent forms of LTP and LTD. Here we studied age-associated changes in mGluR-dependent LTP and LTD in the APP/PS1 mouse model of AD and in Octodon degu, a rodent model of aging that exhibits features of AD. At 2 months of age, APP/PS1 mouse exhibited robust mGluR-dependent LTP and LTD that was completely lost by the 8th month of age. The expression of mGluR protein in the hippocampus of APP/PS1 mice was not affected, consistent with previous findings indicating the uncoupling of the plasticity cascade from mGluR5 activation. In O. degu, the average mGluR-LTD magnitude is reduced by half by the 3 rd year of age. In aged O. degu individuals, the reduced mGluR-LTD correlated with reduced performance in a radial arm maze task. Altogether these findings support the idea that the preservation of mGluR-dependent synaptic plasticity is essential for the preservation of learning capacity during aging.

Uniform resistive switching and highly stable synaptic characteristics of HfOx sandwiched TaOx-based memristor for neuromorphic system

Emerging nanoscale devices, including memristors, have been extensively studied to implement biological synaptic functions such as learning and plasticity, which are the fundamental building blocks of brain-inspired neuromorphic computing. The memristor with analog switching ability exhibits linear tuning of weight during neural network training is a desirable synaptic device behavior. The importance of inserting a HfOx sandwiched layer in a TaOx/HfOx/TaOx memristor is to achieve analog set/reset operation along with improved spatial/temporal switching uniformity. The optimal resistive switching (RS) behavior can be attributed to asymmetric oxygen vacancy distribution in the stacked structure leading to the formation of an hourglass-shaped conductive filament. Furthermore, confining filament formation/rapture in the narrow fixed region displays superior endurance characteristics (dc cycles >2000 and ac cycles > 106) and uniform resistive switching with the set (reset) voltage variation constrained to 1.8 (2.9) %. Paired-pulse facilitation (PPF), a form of short-term synaptic plasticity is stimulated to replicate bio-synapse behavior. The stable long-term potentiation (LTP) and depression (LTD) behavior for more than 1000 epochs (>105 pulses) with excellent symmetry and linearity is achieved with 50 ns voltage pulse stimulation. The pattern recognition accuracy of 93% was achieved for an image of size 10 × 10 pixels after 13 epochs by deploying 100 synapses in Hopfield Neural Network (HNN) simulation. This comprehensive study demonstrates that the HfOx-inserted TaOx memristor has tremendous potential for application in future neuromorphic computing.

Long-Term Synaptic Plasticity Tunes the Gain of Information Channels through the Cerebellum Granular Layer.

A central hypothesis on brain functioning is that long-term potentiation (LTP) and depression (LTD) regulate the signals transfer function by modifying the efficacy of synaptic transmission. In the cerebellum, granule cells have been shown to control the gain of signals transmitted through the mossy fiber pathway by exploiting synaptic inhibition in the glomeruli. However, the way LTP and LTD control signal transformation at the single-cell level in the space, time and frequency domains remains unclear. Here, the impact of LTP and LTD on incoming activity patterns was analyzed by combining patch-clamp recordings in acute cerebellar slices and mathematical modeling. LTP reduced the delay, increased the gain and broadened the frequency bandwidth of mossy fiber burst transmission, while LTD caused opposite changes. These properties, by exploiting NMDA subthreshold integration, emerged from microscopic changes in spike generation in individual granule cells such that LTP anticipated the emission of spikes and increased their number and precision, while LTD sorted the opposite effects. Thus, akin with the expansion recoding process theoretically attributed to the cerebellum granular layer, LTP and LTD could implement selective filtering lines channeling information toward the molecular and Purkinje cell layers for further processing.

Highly adaptive and energy efficient neuromorphic computation enabled by deep-spike heterostructure photonic neuro-transistors

Recently, neuromorphic photonics using optical signal as a data domain are considered as a promising solution to realize the next generation neural network platform. Here, metal-chalcogenide/metal oxide semiconductor based photonic neuro-transistors with deep spike-like heterostructure are proposed as a highly adaptive and energy efficient neuromorphic device. In particular, the energy band structure of cadmium sulfide (CdS)/amorphous indium-gallium-zinc-oxide (a-IGZO) heterojunction is engineered via mediating the anion-to-cation ratio of CdS films. It is revealed that the S/Cd ratio is able to determine the work function of the film which consequently causes a variation in the degree of band-bending at the heterointerface. Using a CdS film with optimized S/Cd ratio (CdS1.2), deep spike-like heterostructure (DHS) can be constructed which enables efficient accumulation of photo-generated charge carriers and the emulation of biological synaptic functions including long-term potentiation (LTP) and depression (LTD) behaviors. Also, the a-IGZO/CdS1.2 DHS transistor exhibits low non-linearity value for LTP (1.1) and less energy consumption (45.04 pJ). Furthermore, 7 × 7 opteoelectronic neuromorphic arrays are successfully implemented to exhibit possibility of realization of hardware-based weight pixel training. In addition, the a-IGZO/CdS1.2 DHS transistor shows a high accuracy for image pattern recognition (85.96%) based on the artificial neural network simulation, proving the feasibility in the artificial intelligent systems.

Selective endocytosis of Ca2+-permeable AMPARs by the Alzheimer's disease risk factor CALM bidirectionally controls synaptic plasticity.

AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission, and the plastic modulation of their surface levels determines synaptic strength. AMPARs of different subunit compositions fulfill distinct roles in synaptic long-term potentiation (LTP) and depression (LTD) to enable learning. Largely unknown endocytic mechanisms mediate the subunit-selective regulation of the surface levels of GluA1-homomeric Ca2+-permeable (CP) versus heteromeric Ca2+-impermeable (CI) AMPARs. Here, we report that the Alzheimer’s disease risk factor CALM controls the surface levels of CP-AMPARs and thereby reciprocally regulates LTP and LTD in vivo to modulate learning. We show that CALM selectively facilitates the endocytosis of ubiquitinated CP-AMPARs via a mechanism that depends on ubiquitin recognition by its ANTH domain but is independent of clathrin. Our data identify CALM and related ANTH domain–containing proteins as the core endocytic machinery that determines the surface levels of CP-AMPARs to bidirectionally control synaptic plasticity and modulate learning in the mammalian brain.

Anti-inflammatory drugs prevent memory and hippocampal plasticity deficits following initial binge-like alcohol exposure in adolescent male rats.

Binge drinking during adolescence impairs learning and memory on the long term, and many studies suggest a role of neuroinflammation. However, whether neuroinflammation occurs after the very first exposures to alcohol remains unclear, while initial alcohol exposure impairs learning for several days in male rats. To investigate the role of neuroinflammation in the effects of only two binge-like episodes on learning and on neuronal plasticity in adolescent male rat hippocampus. Animals received two ethanol i.p. injections (3g/kg) 9h apart. Forty-eight hours later, we recorded long-term depression (LTD) and potentiation (LTP) in CA1 area of hippocampus slices. In isolated CA1, we measured immunolabelings for microglial activation and Toll-like receptor 4 (TLR4) and mRNA levels for several cytokines. Forty-eight hours after the two binges, rats performed worse than control rats in novel object recognition, LTD was reduced, LTP was increased, and excitatory neurotransmission was more sensitive to an antagonist of the GluN2B subunit of the NMDA receptor. Exposure to ethanol with minocycline or indomethacin, two anti-inflammatory drugs, or with a TLR4 antagonist, prevented all effects of ethanol. Immunolabelings at 48h showed a reduction of neuronal TLR4 that was prevented by minocycline pretreatment, while microglial reactivity was undetected and inflammatory cytokines mRNA levels were unchanged. Two binge-like ethanol exposures during adolescence in rat involved neuroinflammation leading to changes in TLR4 expression and in GluN2B functioning inducing disturbances in synaptic plasticity and cognitive deficits. Anti-inflammatory drugs are good candidates to prevent brain function and memory deficits induced by few binge-drinking episodes.

ReSe2-Based RRAM and Circuit-Level Model for Neuromorphic Computing

Resistive random-access memory (RRAM) devices have drawn increasing interest for the simplicity of its structure, low power consumption and applicability to neuromorphic computing. By combining analog computing and data storage at the device level, neuromorphic computing system has the potential to meet the demand of computing power in applications such as artificial intelligence (AI), machine learning (ML) and Internet of Things (IoT). Monolayer rhenium diselenide (ReSe2), as a two-dimensional (2D) material, has been reported to exhibit non-volatile resistive switching (NVRS) behavior in RRAM devices with sub-nanometer active layer thickness. In this paper, we demonstrate stable multiple-step RESET in ReSe2 RRAM devices by applying different levels of DC electrical bias. Pulse measurement has been conducted to study the neuromorphic characteristics. Under different height of stimuli, the ReSe2 RRAM devices have been found to switch to different resistance states, which shows the potentiation of synaptic applications. Long-term potentiation (LTP) and depression (LTD) have been demonstrated with the gradual resistance switching behaviors observed in long-term plasticity programming. A Verilog-A model is proposed based on the multiple-step resistive switching behavior. By implementing the LTP/LTD parameters, an artificial neural network (ANN) is constructed for the demonstration of handwriting classification using Modified National Institute of Standards and Technology (MNIST) dataset.

LIM-Kinases in Synaptic Plasticity, Memory, and Brain Diseases.

Learning and memory require structural and functional modifications of synaptic connections, and synaptic deficits are believed to underlie many brain disorders. The LIM-domain-containing protein kinases (LIMK1 and LIMK2) are key regulators of the actin cytoskeleton by affecting the actin-binding protein, cofilin. In addition, LIMK1 is implicated in the regulation of gene expression by interacting with the cAMP-response element-binding protein. Accumulating evidence indicates that LIMKs are critically involved in brain function and dysfunction. In this paper, we will review studies on the roles and underlying mechanisms of LIMKs in the regulation of long-term potentiation (LTP) and depression (LTD), the most extensively studied forms of long-lasting synaptic plasticity widely regarded as cellular mechanisms underlying learning and memory. We will also discuss the involvement of LIMKs in the regulation of the dendritic spine, the structural basis of synaptic plasticity, and memory formation. Finally, we will discuss recent progress on investigations of LIMKs in neurological and mental disorders, including Alzheimer’s, Parkinson’s, Williams–Beuren syndrome, schizophrenia, and autism spectrum disorders.

Conditional knockout of MET receptor tyrosine kinase in cortical excitatory neurons leads to enhanced learning and memory in young adult mice but early cognitive decline in older adult mice

Human genetic studies established MET gene as a risk factor for autism spectrum disorders. We have previously shown that signaling mediated by MET receptor tyrosine kinase, expressed in early postnatal developing forebrain circuits, controls glutamatergic neuron morphological development, synapse maturation, and cortical critical period plasticity. Here we investigated how MET signaling affects synaptic plasticity, learning and memory behavior, and whether these effects are age-dependent. We found that in young adult (postnatal 2–3 months) Met conditional knockout (Metfx/fx:emx1cre, cKO) mice, the hippocampus exhibits elevated plasticity, measured by increased magnitude of long-term potentiation (LTP) and depression (LTD) in hippocampal slices. Surprisingly, in older adult cKO mice (10–12 months), LTP and LTD magnitudes were diminished. We further conducted a battery of behavioral tests to assess learning and memory function in cKO mice and littermate controls. Consistent with age-dependent LTP/LTD findings, we observed enhanced spatial memory learning in 2–3 months old young adult mice, assessed by hippocampus-dependent Morris water maze test, but impaired spatial learning in 10–12 months mice. Contextual and cued learning were further assessed using a Pavlovian fear conditioning test, which also revealed enhanced associative fear acquisition and extinction in young adult mice, but impaired fear learning in older adult mice. Lastly, young cKO mice also exhibited enhanced motor learning. Our results suggest that a shift in the window of synaptic plasticity and an age-dependent early cognitive decline may be novel circuit pathophysiology for a well-established autism genetic risk factor.

Implementation of Neuro-Memristive Synapse for Long-and Short-Term Bio-Synaptic Plasticity.

In this paper, we propose a complex neuro-memristive synapse that exhibits the physiological acts of synaptic potentiation and depression of the human-brain. Specifically, the proposed neuromorphic synapse efficiently imitates the synaptic plasticity, especially long-term potentiation (LTP) and depression (LTD), and short-term facilitation (STF) and depression (STD), phenomena of a biological synapse. Similar to biological synapse, the short- or long-term potentiation (STF and LTP) or depression (STD or LTD) of the memristive synapse are distinguished on the basis of time or repetition of input cycles. The proposed synapse is also designed to exhibit the effect of reuptake and neurotransmitters diffusion processes of a bio-synapse. In addition, it exhibits the distinct bio-realistic attributes, i.e., strong stimulation, exponentially decaying conductance trace of synapse, and voltage dependent synaptic responses, of a neuron. The neuro-memristive synapse is designed in SPICE and its bio-realistic functionalities are demonstrated via various simulations.

Binding of Filamentous Actin to CaMKII as Potential Regulation Mechanism of Bidirectional Synaptic Plasticity by \u03b2 CaMKII in Cerebellar Purkinje Cells

Calcium-calmodulin dependent protein kinase II (CaMKII) regulates many forms of synaptic plasticity, but little is known about its functional role during plasticity induction in the cerebellum. Experiments have indicated that the β isoform of CaMKII controls the bidirectional inversion of plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in cerebellar cortex. Because the cellular events that underlie these experimental findings are still poorly understood, we developed a simple computational model to investigate how β CaMKII regulates the direction of plasticity in cerebellar PCs. We present the first model of AMPA receptor phosphorylation that simulates the induction of long-term depression (LTD) and potentiation (LTP) at the PF-PC synapse. Our simulation results suggest that the balance of CaMKII-mediated phosphorylation and protein phosphatase 2B (PP2B)-mediated dephosphorylation of AMPA receptors can determine whether LTD or LTP occurs in cerebellar PCs. The model replicates experimental observations that indicate that β CaMKII controls the direction of plasticity at PF-PC synapses, and demonstrates that the binding of filamentous actin to CaMKII can enable the β isoform of the kinase to regulate bidirectional plasticity at these synapses.

Pull-push neuromodulation of cortical plasticity enables rapid bi-directional shifts in ocular dominance.

Neuromodulatory systems are essential for remodeling glutamatergic connectivity during experience-dependent cortical plasticity. This permissive/enabling function of neuromodulators has been associated with their capacity to facilitate the induction of Hebbian forms of long-term potentiation (LTP) and depression (LTD) by affecting cellular and network excitability. In vitro studies indicate that neuromodulators also affect the expression of Hebbian plasticity in a pull-push manner: receptors coupled to the G-protein Gs promote the expression of LTP at the expense of LTD, and Gq-coupled receptors promote LTD at the expense of LTP. Here we show that pull-push mechanisms can be recruited in vivo by pairing brief monocular stimulation with pharmacological or chemogenetical activation of Gs- or Gq-coupled receptors to respectively enhance or reduce neuronal responses in primary visual cortex. These changes were stable, inducible in adults after the termination of the critical period for ocular dominance plasticity, and can rescue deficits induced by prolonged monocular deprivation.

Phosphorylation-Dependent Regulation of Ca2+-Permeable AMPA Receptors During Hippocampal Synaptic Plasticity.

Experience-dependent learning and memory require multiple forms of plasticity at hippocampal and cortical synapses that are regulated by N-methyl-D-aspartate receptors (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (NMDAR, AMPAR). These plasticity mechanisms include long-term potentiation (LTP) and depression (LTD), which are Hebbian input-specific mechanisms that rapidly increase or decrease AMPAR synaptic strength at specific inputs, and homeostatic plasticity that globally scales-up or -down AMPAR synaptic strength across many or even all inputs. Frequently, these changes in synaptic strength are also accompanied by a change in the subunit composition of AMPARs at the synapse due to the trafficking to and from the synapse of receptors lacking GluA2 subunits. These GluA2-lacking receptors are most often GluA1 homomeric receptors that exhibit higher single-channel conductance and are Ca2+-permeable (CP-AMPAR). This review article will focus on the role of protein phosphorylation in regulation of GluA1 CP-AMPAR recruitment and removal from hippocampal synapses during synaptic plasticity with an emphasis on the crucial role of local signaling by the cAMP-dependent protein kinase (PKA) and the Ca2+calmodulin-dependent protein phosphatase 2B/calcineurin (CaN) that is coordinated by the postsynaptic scaffold protein A-kinase anchoring protein 79/150 (AKAP79/150).

Tyrosine phosphorylation of the AMPA receptor subunit GluA2 gates homeostatic synaptic plasticity

Hebbian plasticity, comprised of long-term potentiation (LTP) and depression (LTD), allows neurons to encode and respond to specific stimuli; while homeostatic synaptic scaling is a counterbalancing mechanism that enables the maintenance of stable neural circuits. Both types of synaptic plasticity involve the control of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) abundance, which is modulated by AMPAR phosphorylation. To address the necessity of GluA2 phospho-Y876 in synaptic plasticity, we generated phospho-deficient GluA2 Y876F knock-in mice. We show that, while GluA2 phospho-Y876 is not necessary for Hebbian plasticity, it is essential for both in vivo and in vitro homeostatic upscaling. Bidirectional changes in GluA2 phospho-Y876 were observed during homeostatic scaling, with a decrease during downscaling and an increase during upscaling. GluA2 phospho-Y876 is necessary for synaptic accumulation of glutamate receptor interacting protein 1 (GRIP1), a crucial scaffold protein that delivers AMPARs to synapses, during upscaling. Furthermore, increased phosphorylation at GluA2 Y876 increases GluA2 binding to GRIP1. These results demonstrate that AMPAR trafficking during homeostatic upscaling can be gated by a single phosphorylation site on the GluA2 subunit.