Mechanisms Of Synaptic Plasticity Research Articles

History and Future Directions of rTMS for Treatment of Depressive Disorders

History and Future Directions of rTMS for Treatment of Depressive Disorders

Visual Cortical Plasticity: Molecular Mechanisms as Revealed by Induction Paradigms in Rodents

Assessing the molecular mechanism of synaptic plasticity in the cortex is vital for identifying potential targets in conditions marked by defective plasticity. In plasticity research, the visual cortex represents a target model for intense investigation, partly due to the availability of different in vivo plasticity-induction protocols. Here, we review two major protocols: ocular-dominance (OD) and cross-modal (CM) plasticity in rodents, highlighting the molecular signaling pathways involved. Each plasticity paradigm has also revealed the contribution of different populations of inhibitory and excitatory neurons at different time points. Since defective synaptic plasticity is common to various neurodevelopmental disorders, the potentially disrupted molecular and circuit alterations are discussed. Finally, new plasticity paradigms are presented, based on recent evidence. Stimulus-selective response potentiation (SRP) is one of the paradigms addressed. These options may provide answers to unsolved neurodevelopmental questions and offer tools to repair plasticity defects.

Synaptic self-organization of spatio-temporal pattern selectivity.

Spiking model neurons can be set up to respond selectively to specific spatio-temporal spike patterns by optimization of their input weights. It is unknown, however, if existing synaptic plasticity mechanisms can achieve this temporal mode of neuronal coding and computation. Here it is shown that changes of synaptic efficacies which tend to balance excitatory and inhibitory synaptic inputs can make neurons sensitive to particular input spike patterns. Simulations demonstrate that a combination of Hebbian mechanisms, hetero-synaptic plasticity and synaptic scaling is sufficient for self-organizing sensitivity for spatio-temporal spike patterns that repeat in the input. In networks inclusion of hetero-synaptic plasticity that depends on the pre-synaptic neurons leads to specialization and faithful representation of pattern sequences by a group of target neurons. Pattern detection is robust against a range of distortions and noise. The proposed combination of Hebbian mechanisms, hetero-synaptic plasticity and synaptic scaling is found to protect the memories for specific patterns from being overwritten by ongoing learning during extended periods when the patterns are not present. This suggests a novel explanation for the long term robustness of memory traces despite ongoing activity with substantial synaptic plasticity. Taken together, our results promote the plausibility of precise temporal coding in the brain.

Synaptic Plasticity Abnormalities in Fetal Alcohol Spectrum Disorders.

The brain's ability to strengthen or weaken synaptic connections is often termed synaptic plasticity. It has been shown to function in brain remodeling following different types of brain damage (e.g., drugs of abuse, alcohol use disorders, neurodegenerative diseases, and inflammatory conditions). Although synaptic plasticity mechanisms have been extensively studied, how neural plasticity can influence neurobehavioral abnormalities in alcohol use disorders (AUDs) is far from being completely understood. Alcohol use during pregnancy and its harmful effects on the developing offspring are major public health, social, and economic challenges. The significant attribute of prenatal alcohol exposure on offspring is damage to the central nervous system (CNS), causing a range of synaptic structural, functional, and behavioral impairments, collectively called fetal alcohol spectrum disorder (FASD). Although the synaptic mechanisms in FASD are limited, emerging evidence suggests that FASD pathogenesis involves altering a set of molecules involved in neurotransmission, myelination, and neuroinflammation. These studies identify several immediate and long-lasting changes using many molecular approaches that are essential for synaptic plasticity and cognitive function. Therefore, they can offer potential synaptic targets for the many neurobehavioral abnormalities observed in FASD. In this review, we discuss the substantial research progress in different aspects of synaptic and molecular changes that can shed light on the mechanism of synaptic dysfunction in FASD. Increasing our understanding of the synaptic changes in FASD will significantly advance our knowledge and could provide a basis for finding novel therapeutic targets and innovative treatment strategies.

Mechanisms That Underlie Expression of Estradiol-Induced Excitatory Synaptic Potentiation in the Hippocampus Differ between Males and Females.

17β-estradiol (E2) is synthesized in the hippocampus of both sexes and acutely potentiates excitatory synapses in each sex. Previously, we found that the mechanisms for initiation of E2-induced synaptic potentiation differ between males and females, including in the molecular signaling involved. Here, we used electrical stimulation and two-photon glutamate uncaging in hippocampal slices from adult male and female rats to investigate whether the downstream consequences of distinct molecular signaling remain different between the sexes or converge to the same mechanism(s) of expression of potentiation. This showed that synaptic activity is necessary for expression of E2-induced potentiation in females but not males, which paralleled a sex-specific requirement in females for calcium-permeable AMPARs (cpAMPARs) to stabilize potentiation. Nonstationary fluctuation analysis of two-photon evoked unitary synaptic currents showed that the postsynaptic component of E2-induced potentiation occurs either through an increase in AMPAR conductance or in nonconductive properties of AMPARs (number of channels × open probability) and never both at the same synapse. In females, most synapses (76%) were potentiated via increased AMPAR conductance, whereas in males, more synapses (60%) were potentiated via an increase in nonconductive AMPAR properties. Inhibition of cpAMPARs eliminated E2-induced synaptic potentiation in females, whereas some synapses in males were unaffected by cpAMPAR inhibition; these synapses in males potentiated exclusively via increased AMPAR nonconductive properties. This sex bias in expression mechanisms of E2-induced synaptic potentiation underscores the concept of latent sex differences in mechanisms of synaptic plasticity in which the same outcome in each sex is achieved through distinct underlying mechanisms.SIGNIFICANCE STATEMENT Estrogens are synthesized in the brains of both sexes and potentiate excitatory synapses to the same degree in each sex. Despite this apparent similarity, the molecular signaling that initiates estrogen-induced synaptic potentiation differs between the sexes. Here we show that these differences extend to the mechanisms of expression of synaptic potentiation and result in distinct patterns of postsynaptic neurotransmitter receptor modulation in each sex. Such latent sex differences, in which the same outcome is achieved through distinct underlying mechanisms in males versus females, indicate that molecular mechanisms targeted for drug development may differ between the sexes even in the absence of an overt sex difference in behavior or disease.

Long-term memory, synaptic plasticity and dopamine in rodent medial prefrontal cortex: Role in executive functions.

Mnemonic functions, supporting rodent behavior in complex tasks, include both long-term and (short-term) working memory components. While working memory is thought to rely on persistent activity states in an active neural network, long-term memory and synaptic plasticity contribute to the formation of the underlying synaptic structure, determining the range of possible states. Whereas, the implication of working memory in executive functions, mediated by the prefrontal cortex (PFC) in primates and rodents, has been extensively studied, the contribution of long-term memory component to these tasks received little attention. This review summarizes available experimental data and theoretical work concerning cellular mechanisms of synaptic plasticity in the medial region of rodent PFC and the link between plasticity, memory and behavior in PFC-dependent tasks. A special attention is devoted to unique properties of dopaminergic modulation of prefrontal synaptic plasticity and its contribution to executive functions.

Intranasal Administration of KYCCSRK Peptide Rescues Brain Insulin Signaling Activation and Reduces Alzheimer's Disease-like Neuropathology in a Mouse Model for Down Syndrome.

Down syndrome (DS) is the most frequent genetic cause of intellectual disability and is strongly associated with Alzheimer's disease (AD). Brain insulin resistance greatly contributes to AD development in the general population and previous studies from our group showed an early accumulation of insulin resistance markers in DS brain, already in childhood, and even before AD onset. Here we tested the effects promoted in Ts2Cje mice by the intranasal administration of the KYCCSRK peptide known to foster insulin signaling activation by directly interacting and activating the insulin receptor (IR) and the AKT protein. Therefore, the KYCCSRK peptide might represent a promising molecule to overcome insulin resistance. Our results show that KYCCSRK rescued insulin signaling activation, increased mitochondrial complexes levels (OXPHOS) and reduced oxidative stress levels in the brain of Ts2Cje mice. Moreover, we uncovered novel characteristics of the KYCCSRK peptide, including its efficacy in reducing DYRK1A (triplicated in DS) and BACE1 protein levels, which resulted in reduced AD-like neuropathology in Ts2Cje mice. Finally, the peptide elicited neuroprotective effects by ameliorating synaptic plasticity mechanisms that are altered in DS due to the imbalance between inhibitory vs. excitatory currents. Overall, our results represent a step forward in searching for new molecules useful to reduce intellectual disability and counteract AD development in DS.

A synaptic plasticity induced change in synaptic intensity variation and neurodynamic transition during awakening-sleep cycle

It has been found experimentally that learning during wakefulness leads to a net enhancement of synaptic strength, accompanied by the neural dynamical transition from tonic to bursting firing, while the net synaptic strength decreases to a baseline level during sleep, accompanied by the transition from bursting to tonic firing. In this paper, we establish a model of synaptic plasticity, which can realize synaptic strength changes and neural dynamical transitions in wakefulness-sleep cycle by using the coupled Hindmarsh-Rose neurons. Through numerical simulation and theoretical analysis, it is further found that the average synaptic weight of the neural network can reach a stable value during either prolonged wakefulness or prolonged sleep, which depends on the ratio of some specific parameters in the model. Particularly, the synaptic weight exhibits a stable log-normal distribution observed in a real neural system, when the average synaptic weight reaches a stable value. Moreover, the fluctuation of this weight distribution is positively correlated with the fluctuation of noise in the synaptic plasticity model. The provided model of the synaptic plasticity and its dynamics results can provide a theoretical reference for studying the physiological mechanism of synaptic plasticity and neuronal firings during the wakefulness-sleep cycle, and they are expected to have potential applications in the development of therapeutic interventions for sleep disorders.

Tunable plasticity in functionalized honeycomb synaptic memristor for neurocomputing

Tunable plasticity is one of the important features in synapses and plays a key role in neuromorphic computing (neurocomputing, NC), maintaining a stable pulse neural network environment, and realizing accurate image recognition. Herein, a functionalized honeycomb-like synaptic memristor (HLSM) composed of porous silicon oxide incorporated with MoS2 quantum dots (QDs) is fabricated and the synaptic properties such as paired-pulse facilitation (PPF), post-tetanic potentiation (PTP), learning-forgetting behavior, and spike-timing-dependent plasticity (STDP) are simulated. A critical characteristic of short/long-term plasticity (SLTP) is observed from the HLSM device for the sliding frequency threshold between 200 μs and 10 ms and tunable synaptic plasticity is realized without gate voltage regulation. An artificial neural network (ANN) based on the potentiation/depression characteristics is designed theoretically and the recognition rate is observed to increase from 54.2% to 91.8% by simply adjusting the input frequency. The underlying mechanism of the tunable synaptic plasticity is proposed and discussed by taking advantage of the honeycomb structure on fluid buffering and acceleration. The results and theoretical understanding are expected to accelerate the application in NC to image recognition.

Synaptic plasticity in schizophrenia pathophysiology.

Schizophrenia is a severe neuropsychiatric syndrome with psychotic behavioral abnormalities and marked cognitive deficits. It is widely accepted that genetic and environmental factors contribute to the onset of schizophrenia. However, the etiology and pathology of the disease remain largely unexplored. Recently, the synaptopathology and the dysregulated synaptic plasticity and function have emerging as intriguing and prominent biological mechanisms of schizophrenia pathogenesis. Synaptic plasticity is the ability of neurons to change the strength of their connections in response to internal or external stimuli, which is essential for brain development and function, learning and memory, and vast majority of behavior responses relevant to psychiatric diseases including schizophrenia. Here, we reviewed molecular and cellular mechanisms of the multiple forms synaptic plasticity, and the functional regulations of schizophrenia-risk factors including disease susceptible genes and environmental alterations on synaptic plasticity and animal behavior. Recent genome-wide association studies have provided fruitful findings of hundreds of risk gene variances associated with schizophrenia, thus further clarifying the role of these disease-risk genes in synaptic transmission and plasticity will be beneficial to advance our understanding of schizophrenia pathology, as well as the molecular mechanism of synaptic plasticity.

Astrocytes mediate long-lasting synaptic regulation of ventral tegmental area dopamine neurons.

The plasticity of glutamatergic transmission in the ventral tegmental area (VTA) represents a fundamental mechanism in the modulation of dopamine neuron burst firing and phasic dopamine release at target regions. These processes encode basic behavioral responses, including locomotor activity, learning and motivated behaviors. Here we describe a hitherto unidentified mechanism of long-term synaptic plasticity in mouse VTA. We found that the burst firing in individual dopamine neurons induces a long-lasting potentiation of excitatory synapses on adjacent dopamine neurons that crucially depends on Ca2+ elevations in astrocytes, mediated by endocannabinoid CB1 and dopamine D2 receptors co-localized at the same astrocytic process, and activation of pre-synaptic metabotropic glutamate receptors. Consistent with these findings, selective in vivo activation of astrocytes increases the burst firing of dopamine neurons in the VTA and induces locomotor hyperactivity. Astrocytes play, therefore, a key role in the modulation of VTA dopamine neuron functional activity.

Expression and Interaction Proteomics of GluA1- and GluA3-Subunit-Containing AMPARs Reveal Distinct Protein Composition.

The AMPA glutamate receptor (AMPAR) is the major type of synaptic excitatory ionotropic receptor in the brain. AMPARs have four different subunits, GluA1-4 (each encoded by different genes, Gria1, Gria2, Gria3 and Gria4), that can form distinct tetrameric assemblies. The most abundant AMPAR subtypes in the hippocampus are GluA1/2 and GluA2/3 heterotetramers. Each subtype contributes differentially to mechanisms of synaptic plasticity, which may be in part caused by how these receptors are regulated by specific associated proteins. A broad range of AMPAR interacting proteins have been identified, including the well-studied transmembrane AMPA receptor regulatory proteins TARP-γ2 (also known as Stargazin) and TARP-γ8, Cornichon homolog 2 (CNIH-2) and many others. Several interactors were shown to affect biogenesis, AMPAR trafficking, and channel properties, alone or in distinct assemblies, and several revealed preferred binding to specific AMPAR subunits. To date, a systematic specific interactome analysis of the major GluA1/2 and GluA2/3 AMPAR subtypes separately is lacking. To reveal interactors belonging to specific AMPAR subcomplexes, we performed both expression and interaction proteomics on hippocampi of wildtype and Gria1- or Gria3 knock-out mice. Whereas GluA1/2 receptors co-purified TARP-γ8, synapse differentiation-induced protein 4 (SynDIG4, also known as Prrt1) and CNIH-2 with highest abundances, GluA2/3 receptors revealed strongest co-purification of CNIH-2, TARP-γ2, and Noelin1 (or Olfactomedin-1). Further analysis revealed that TARP-γ8-SynDIG4 interact directly and co-assemble into an AMPAR subcomplex especially at synaptic sites. Together, these data provide a framework for further functional analysis into AMPAR subtype specific pathways in health and disease.

Neuregulins: subcellular localization, signaling pathways and their relationship with neuroplasticity and neurological diseases

Neuregulins (NRGs) and their cognate ErbB receptors (ErbB2–ErbB4) constitute a vast group of proteins encoded by six different genes (NRG1–6) and many isoforms with critical roles in the development and functioning of the nervous system. NRGs are known to regulate important processes in the nervous system like neural development, neuronal differentiation, neurite outgrowth, and specification. These factors are involved in the regulation of neurotransmission pathways and the modulation of several forms of synaptic plasticity. Due to NRGs’ role in synaptic plasticity, defects in their normal functioning are translated into altered signaling networks, which have been linked to susceptibility to developing psychiatric disorders like schizophrenia (SZ), autism, depression, and bipolar disorders. Additionally, deviation of the NRG normal functioning is involved in neurological diseases like Alzheimer’s and Parkinson’s disease. Contrastingly, NRG/ErbB signaling is also involved in the recovery after traumatic brain injuries (e.g., ischemic stroke). The NRG/ErbB signaling complex is highly unusual because the ligands (mainly NRG1–NRG3, with their multiple isoforms) and receptors (ErbB2–ErbB4) can orchestrate vast signaling complexes, with a wide reach within the processes that govern the development and appropriate function of the nervous system. This may explain why NRGs and ErbB receptor genes have been linked to complex brain disorders, like SZ. This review, are discussed important aspects of NRG and their relevance for nervous system functioning, including 1) subcellular localization, 2) signaling pathways involved in neuronal functions, 3) effect on neurite development and synapse formation, 4) modulation of some mechanisms of synaptic plasticity [long-term potentiation (LTP), depotentiation, long-term depression (LTD)] and 5) roles of NRGs in some neurological diseases. This review intends to present a summary of the main findings about this family of proteins, which might position them as one of the master regulators of brain functioning.

Structural plasticity driven by task performance leads to criticality signatures in neuromorphic oscillator networks

Oscillator networks rapidly become one of the promising vehicles for energy-efficient computing due to their intrinsic parallelism of execution. The criticality property of the oscillator-based networks is regarded to be essential for performing complex tasks. There are numerous bio-inspired synaptic and structural plasticity mechanisms available, especially for spiking neural networks, which can drive the network towards the criticality. However, there is no solid connection between these self-adaption mechanisms and the task performance, and it is not clear how and why particular self-adaptation mechanisms contribute to the solution of the task, although their relation to criticality is understood. Here we propose an evolutionary approach for the structural plasticity that relies solely on the task performance and does not contain any task-independent adaptation mechanisms, which usually contribute towards the criticality of the network. As a driver for the structural plasticity, we use a direct binary search guided by the performance of the classification task that can be interpreted as an interaction of the network with the environment. Remarkably, such interaction with the environment brings the network to criticality, although this property was not a part of the objectives of the employed structural plasticity mechanism. This observation confirms a duality of criticality and task performance, and legitimizes internal activity-dependent plasticity mechanisms from the viewpoint of evolution as mechanisms contributing to the task performance, but following the dual route. Finally, we analyze the trained network against task-independent information-theoretic measures and identify the interconnection graph’s entropy to be an essential ingredient for the classification task performance and network’s criticality.

Applying the Properties of Neurons in Machine Learning: A Brain-like Neural Model with Interactive Stimulation for Data Classification

Some neural models achieve outstanding results in image recognition, semantic segmentation and natural language processing. However, their classification performance on structured and small-scale datasets that do not involve feature extraction is worse than that of traditional algorithms, although they require more time to train. In this paper, we propose a brain-like neural model with interactive stimulation (NMIS) that focuses on data classification. It consists of a primary neural field and a senior neural field that play different cognitive roles. The former is used to correspond to real instances in the feature space, and the latter stores the category pattern. Neurons in the primary field exchange information through interactive stimulation and their activation is transmitted to the senior field via inter-field interaction, simulating the mechanisms of neuronal interaction and synaptic plasticity, respectively. The proposed NMIS is biologically plausible and does not involve complex optimization processes. Therefore, it exhibits better learning ability on small-scale and structured datasets than traditional BP neural networks. For large-scale data classification, a nearest neighbor NMIS (NN_NMIS), an optimized version of NMIS, is proposed to improve computational efficiency. Numerical experiments performed on some UCI datasets show that the proposed NMIS and NN_NMIS are significantly superior to some classification algorithms that are widely used in machine learning.

Changes in regulators of lipid metabolism in the brain: a study of animal models of depression and hypothyroidism

Metabolic disturbances in the brain are assumed to be early changes involved in the pathogenesis of depression, and these alterations may be intensified by a deficiency of thyroid hormones. In contrast to glucose metabolism, the link between altered brain lipids and the pathogenesis of depression is poorly understood, therefore in the present study, we determine transcription factors and enzymes regulating cholesterol and fatty acid biosynthesis in the brain structures in an animal model of depression, hypothyroidism and the coexistence of these diseases.In used model of depression, a decrease in the active form of the transcription factor SREBP-2 in the hippocampus was demonstrated, thus suggesting a reduction in cholesterol biosynthesis. In turn, in the hypothyroidism model, the reduction of cholesterol biosynthesis in the frontal cortex was demonstrated by both the reduction of mature SREBP-2 and the concentration of enzymes involved in cholesterol biosynthesis. The lower expression of LDL receptors in the frontal cortex indicates the restriction of cholesterol uptake into the cells in the model of coexistence of depression and hypothyroidism. Moreover, the identified changes in the levels of SNAP-25, GLP-1R and GLP-2R pointed to disturbances in synaptic plasticity and neuroprotection mechanisms in the examined brain structures.In conclusion, a reduction in cholesterol synthesis in the hippocampus in the model of depression may be the reason for the reduction of synaptic plasticity, whereas a lower level of LDL-R occurring in the frontal cortex in rats from the model of depression and hypothyroidism coexistence could be the reason of anxiogenic and depression-like behaviors.

Purkinje Cell Activity Resonation Generates Rhythmic Behaviors at the Preferred Frequency of 8 Hz.

Neural activity exhibits oscillations, bursts, and resonance, enhancing responsiveness at preferential frequencies. For example, theta-frequency bursting and resonance in granule cells facilitate synaptic transmission and plasticity mechanisms at the input stage of the cerebellar cortex. However, whether theta-frequency bursting of Purkinje cells is involved in generating rhythmic behavior has remained neglected. We recorded and optogenetically modulated the simple and complex spike activity of Purkinje cells while monitoring whisker movements with a high-speed camera of awake, head-fixed mice. During spontaneous whisking, both simple spike activity and whisker movement exhibit peaks within the theta band. Eliciting either simple or complex spikes at frequencies ranging from 0.5 to 28 Hz, we found that 8 Hz is the preferred frequency around which the largest movement is induced. Interestingly, oscillatory whisker movements at 8 Hz were also generated when simple spike bursting was induced at 2 and 4 Hz, but never via climbing fiber stimulation. These results indicate that 8 Hz is the resonant frequency at which the cerebellar-whisker circuitry produces rhythmic whisking.

High-resolution imaging and manipulation of endogenous AMPA receptor surface mobility during synaptic plasticity and learning.

Regulation of synaptic neurotransmitter receptor content is a fundamental mechanism for tuning synaptic efficacy during experience-dependent plasticity and behavioral adaptation. However, experimental approaches to track and modify receptor movements in integrated experimental systems are limited. Exploiting AMPA-type glutamate receptors (AMPARs) as a model, we generated a knock-in mouse expressing the biotin acceptor peptide (AP) tag on the GluA2 extracellular N-terminal. Cell-specific introduction of biotin ligase allows the use of monovalent or tetravalent avidin variants to respectively monitor or manipulate the surface mobility of endogenous AMPAR containing biotinylated AP–GluA2 in neuronal subsets. AMPAR immobilization precluded the expression of long-term potentiation and formation of contextual fear memory, allowing target-specific control of the expression of synaptic plasticity and animal behavior. The AP tag knock-in model offers unprecedented access to resolve and control the spatiotemporal dynamics of endogenous receptors, and opens new avenues to study the molecular mechanisms of synaptic plasticity and learning.

Brain structure and synaptic protein expression alterations after antidepressant treatment in a Wistar–Kyoto rat model of depression

BackgroundStructural MRI has demonstrated brain alterations in depression pathology and antidepressants treatment. While synaptic plasticity has been previously proposed as the potential underlying mechanism of MRI findings at a cellular and molecular scale, there is still insufficient evidence to link the MRI findings and synaptic plasticity mechanisms in depression pathology. MethodsIn this study, a Wistar-Kyoto (WKY) depression rat model was treated with antidepressants (citalopram or Jie-Yu Pills) and tested in a series of behavioral tests and a 7.0 MRI scanner. We then measured dendritic spine density within altered brain regions. We also examined expression of synaptic marker proteins (PSD-95 and SYP). ResultsWKY rats exhibited depression-like behaviors in the sucrose preference test (SPT) and forced swim test (FST), and anxiety-like behaviors in the open field test (OFT). Both antidepressants reversed behavioral changes in SPT and OFT but not in FST. We found a correlation between SPT performance and brain volumes as detected by MRI. All structural changes were consistent with alterations of the corpus callosum (white matter), dendritic spine density, as well as PSD95 and SYP expression at different levels. Two antidepressants similarly reversed these macro- and micro-changes. LimitationsThe single dose of antidepressants was the major limitation of this study. Further studies should focus on the white matter microstructure changes and myelin-related protein alterations, in addition to comparing the effects of ketamine. ConclusionTranslational evidence links structural MRI changes and synaptic plasticity alterations, which promote our understanding of SPT mechanisms and antidepressant response in WKY rats.

Arc weakens synapses by dispersing AMPA receptors from postsynaptic density via modulating PSD phase separation.

In response to stimuli, the immediate early gene product Arc can acutely down-regulate synaptic strength by removing AMPA receptors (AMPARs) from synapses and thus regulate synaptic plasticity. How Arc, a scaffold protein, can specifically facilitate synaptic removal of AMPARs is unknown. We found that Arc directly antagonizes with PSD-95 in binding to TARPs, which are the auxiliary subunits of AMPARs. Arc, in a highly concentration-sensitive manner, acutely disperses TARPs from the postsynaptic density (PSD) condensate formed via phase separation. TARPs with the Ser residue in the "P-S-Y"-motif of its tail phosphorylated are completely refractory from being dispersed by Arc, suggesting that Arc cannot displace AMPARs from PSDs in active synapses. Conversely, strengthening the interaction between Arc and TARPs enhances Arc's capacity in weakening synapses. Thus, Arc can specifically and effectively modulate synaptic AMPAR clustering via modulating PSD phase separation. Our study further suggests that activity-dependent, bi-directional modulation of PSD condensate formation/dispersion represents a general regulatory mechanism for synaptic plasticity.