AMPA receptors

Synaptic changes driven by Hebbian plasticity are unstable and require compensatory mechanisms to homeostatically control neuronal activity. Synaptic scaling regulates the synaptic efficacies to bring individual neurons to a set firing regime [1]. However, the timescales of synaptic scaling are too slow to counterbalance the rapid growth due to Hebbian mechanisms [2]. Heterosynaptic plasticity that operates on timescales similar to Hebbian processes can prevent runaway potentiation [3] but its ability to homeostatically control activity is uncertain. Here, we introduce aggregate scaling, a si

AMPA receptors (AMPARs) mediate fast excitatory neurotransmission and participate in memory formation. Synaptic strength is proportional to the number of AMPARs in the postsynaptic membrane. Previous models of AMPA receptor trafficking can explain their fast, brief incorporation in dendritic spines after LTP induction but offer limited insights into long-lasting changes in AMPAR content at potentiated spines[1,2]. Hence, a unified modeling framework is necessary to understand persistent synaptic changes in AMPAR numbers. Molecular trafficking, such as diffusion, active transport, endo/exocytos

Depression is associated with dysregulated circadian rhythms, but the role of intrinsic clocks in mood-controlling brain regions remains poorly understood. We found increased oscillation of clock negative regulatory loop, as well as a phase shift of Bmal1 expression in the medial prefrontal cortex (mPFC) of a mouse model of depression (depression-like behavior and anhedonia induced by daily 10 min swim sessions for 5 consecutive days). Selective disruption of mPFC clockwork with viral Bmal1KO in CaMK2a excitatory neurons blocks the development of depressive-like phenotype in our model of depre

The recruitment of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors underlies the strengthening of neuronal connectivity during learning and memory. This process is triggered by N-methyl-D-aspartate (NMDA) receptor-dependent postsynaptic Ca2+ influx. Synaptotagmin (Syt)-1 and -7 have been proposed as Ca2+ sensors for AMPA receptor exocytosis, but are functionally redundant. Here we identify a cytosolic C2 domain-containing Ca2+-binding protein Copine-6 that forms a complex with AMPA receptors. Loss of Copine-6 expression impairs activity-induced exocytosis of AMP

…triggering vesicle release and II) AMPA receptors mediating the

Long-term synaptic plasticity (LTP) is the fundamental cellular mechanism which underlies long-term storage of information in neuronal circuits. Synaptic plasticity has mainly been studied on excitatory pyramidal neurons during memory formation. However, GABAergic interneurons are key players in orchestrating the dynamic of excitatory neuronal networks during this process. Thus, the excitatory synapses onto interneurons are central to this control as they constrain pyramidal-cells activity and set synaptic plasticity at excitatory-excitatory synapses. Nonetheless, how, when and where plasticit

Fragile X syndrome (FXS) is the most common inherited form of Intellectual Disability and a leading monogenic cause of autism. FXS results from mutations within the FMR1 gene causing the loss-of-function of the RNA-binding Fragile X Messenger RibonucleoProtein (FMRP). FMRP transports mRNAs along dendrites toward the base of active synapses for their activity-dependent translation. In FXS, the loss-of-function of FMRP leads to a hyper-abundance of dendritic protrusions. Several FMR1 missense mutations identified in patients also lead FXS but how these mutations affect the function of FMRP and l

…AMPA receptors (AMPARs), the major neurotransmitter receptors in the brain, are implicated in the synaptic dysfunction observed in rodent models expressing amyloidogenic APP mutations. AMPARs are proposed to undergo aberrant trafficking, characterized by changes in their subunit composition and subcellular localization. The precise mechanisms underlying the dysregulation of AMPAR trafficking in AD remain poorly understood.Here, we apply

…for its action as calcium permeable AMPA receptors (CP-AMPARs) antagonist. Our study aim to investigate the impact of NASPM on an ex vivo human brain slice neocortex model, focusing on its ability to suppress epileptic activity. While AMPA receptors play a central role in neocortical signaling and neuronal activity, the contribution of CP-AMPARs, particularly in the context of seizure-induced inhibition/excitation imbalance, remains unknown. By applying NASPM to ex vivo human cortex slices, we aimed to investigate its a

…neurexin and the post-synaptic AMPA receptors (Suzuki, Sasakura et al., Science, (2020)). We previousl

…imaging method in acute rat hippocampal slices to map unitary synaptic connections between CA3 neurons by using Voltron, which can detect both action potentials and small subthreshold events, such as unitary EPSPs. These connections are crucial for major hippocampal memory functions; however

…Here, we studied the role of AMPA receptors (AMPARs) in in vitro and in vivo models of prenatal alcohol exposure (PAE). For the in vitro study, immature rat organotypic hippocampal slices were exposed to EtOH (150 mM) for 7 days followed by 24 hours of withdrawal. For the in vivo study, female C57/Bl6 mice were exposed

De novo mutations in STXBP1 are among the most prevalent causes of neurodevelopmental disorders, leading to haploinsufficiency, cortical hyperexcitability, epilepsy, and motor impairments. STXBP1 encodes for Munc18-1, an essential protein for synaptic transmission. In a mouse model of the disease, we found that excitatory synapses, not inhibitory synapses, are impaired during early stages of the disease. Consequently, excitatory synapses fail to recruit parvalbumin-positive (PV) inhibitory interneurons in feedforward inhibitory microcircuits, leading to cortical hyperexcitability. In this stud

Purkinje cells (PCs) are known to express both GluK1 and GluK4 kainate receptor (KAR) subunits, but the exact role of KARs in synaptic information transfer to PCs is unknown. In this study, we discovered that climbing fiber (CF) to PC synapses contain heteromeric GluK1/GluK4 synaptic KARs. Genetic deletion of Grik4, which encodes for GluK4 subunits, resulted in the lack of synaptic but not extrasynaptic KARs, while deletion of Grik1 (GluK1 subunits) eliminated both synaptic and extrasynaptic KARs. Surprisingly, the absence of synaptic KARs led to a significant reduction in the EPSC component m

During Long Term Potentiation (LTP) AMPA receptors (AMPARs) are inserted into the plasma membrane. This form of synaptic plasticity is crucial for many aspects of brain function, including learning and memory. Protein 4.1N (EPB41L1) is a neuronally enriched member of the protein 4.1 family. In primary hippocampal cultures, 4.1N is enriched at the discrete sites of synaptic contact, co-localizing with the postsynaptic density proteins, suggesting a potential functional role for 4.1N as a component of the cytoskeletal architecture of excitatory synapses. 4.1N also directly interacts with the Glu

…characterized by the presence of NMDA receptors and absence of AMPA receptors, hindering fast synaptic transmission (Huang et al, 2009). While typically abundant during early postnatal development, cocaine triggers the de novo generation of silent synapses in the adult brain, thereby establishing new synaptic connections within an already refined circuit (Huang et al, 2009; Huang et al, 2015). During withdrawal, some silent synapses undergo unsilencing by incorporating AMPARs, which crucially contri

…In its silent state, it lacks AMPA receptors (AMPAR), which are incorporated during long-term synaptic potentiation (LTP). In contrast ‘idle-able’ sites contribute to, and regulate, spontaneous transmission. ‘Idled’ AMPARs are in a desensitized-like state and cannot contribute to transmission. They are ‘unidled’ by TCM, an AMPAR desensit

Traditionally, research on AMPA receptors has predominantly focused on GluA1 and GluA2 subunits. However, emerging consensus now emphasizes the pivotal role of GluA3 in specific forms of plasticity and behaviors. Though, most of the research conducted thus far has employed complete knockout animal model of GluA3-encoding gene (GRIA3) where compensatory events during neurodevelopment may obscure GluA3’s function.To better dissect GluA3's contribution to complex behaviors, we employed two in vivo mouse models of GluA3 downregulation in adult mice. First, we chronically administered autoantibodie

The use of molecular imaging, particularly PET and SPECT, has significantly transformed the treatment of schizophrenia with antipsychotic drugs since the late 1980s. It has offered insights into the links between drug target engagement, clinical effects, and side effects. A therapeutic window for receptor occupancy is established for antipsychotics, yet there is a divergence of opinions regarding the importance of blood levels, with many downplaying their significance. As a result, the role of therapeutic drug monitoring (TDM) as a personalized therapy tool is often underrated. Since molecular