Synaptically Targeted Narp Plays an Essential Role in the Aggregation of AMPA Receptors at Excitatory Synapses in Cultured Spinal Neurons

Mutations in IQSEC2 cause intellectual disability (ID), which is often accompanied by seizures and autism. A number of studies have shown that IQSEC2 is an abundant protein in excitatory synapses and plays an important role in neuronal development as well as synaptic plasticity. Here, we review neuronal IQSEC2 signaling with emphasis on those aspects likely to be involved in autism. IQSEC2 is normally bound to N-methyl-D-aspartate (NMDA)-type glutamate receptors via post synaptic density protein 95 (PSD-95). Activation of NMDA receptors results in calcium ion influx and binding to calmodulin present on the IQSEC2 IQ domain. Calcium/calmodulin induces a conformational change in IQSEC2 leading to activation of the SEC7 catalytic domain. GTP is exchanged for GDP on ADP ribosylation factor 6 (ARF6). Activated ARF6 promotes downregulation of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors through a c-jun N terminal kinase (JNK)-mediated pathway. NMDA receptors, AMPA receptors, and PSD-95 are all known to be adversely affected in autism. An IQSEC2 transgenic mouse carrying a constitutively active mutation (A350V) shows autistic features and reduced levels of surface AMPA receptor subunit GluA2. Sec7 activity and AMPA receptor recycling are presented as two targets, which may respond to drug treatment in IQSEC2-associated ID and autism.

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Postsynaptic Neuroligin-1 Mediates Presynaptic Endocytosis During Neuronal Activity

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.744845 ◽

2021 ◽

Vol 14 ◽

Author(s):

Jiaqi Keith Luo ◽

Holly Melland ◽

Jess Nithianantharajah ◽

Sarah L. Gordon

Keyword(s):

Ampa Receptors ◽

Neurotransmitter Release ◽

Synaptic Vesicles ◽

High Fidelity ◽

Excitatory Synapses ◽

Synaptic Efficacy ◽

Molecular Architecture ◽

Adhesion Protein ◽

Presynaptic Nerve Terminal ◽

Presynaptic Release

Fast, high-fidelity neurotransmission and synaptic efficacy requires tightly regulated coordination of pre- and postsynaptic compartments and alignment of presynaptic release sites with postsynaptic receptor nanodomains. Neuroligin-1 (Nlgn1) is a postsynaptic cell-adhesion protein exclusively localised to excitatory synapses that is crucial for coordinating the transsynaptic alignment of presynaptic release sites with postsynaptic AMPA receptors as well as postsynaptic transmission and plasticity. However, little is understood about whether the postsynaptic machinery can mediate the molecular architecture and activity of the presynaptic nerve terminal, and thus it remains unclear whether there are presynaptic contributions to Nlgn1-dependent control of signalling and plasticity. Here, we employed a presynaptic reporter of neurotransmitter release and synaptic vesicle dynamics, synaptophysin-pHluorin (sypHy), to directly assess the presynaptic impact of loss of Nlgn1. We show that lack of Nlgn1 had no effect on the size of the readily releasable or entire recycling pool of synaptic vesicles, nor did it impact exocytosis. However, we observed significant changes in the retrieval of synaptic vesicles by compensatory endocytosis, specifically during activity. Our data extends growing evidence that synaptic adhesion molecules critical for forming transsynaptic scaffolds are also important for regulating activity-induced endocytosis at the presynapse.

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Neuronal signature of social novelty exploration in the VTA: implication for Autism Spectrum Disorder

10.1101/280537 ◽

2018 ◽

Cited By ~ 2

Author(s):

Sebastiano Bariselli ◽

Hanna Hörnberg ◽

Clément Prévost-Solié ◽

Stefano Musardo ◽

Laetitia Hatstatt-Burkle ◽

...

Keyword(s):

Social Interaction ◽

Ampa Receptors ◽

Behavioral Responses ◽

Autism Spectrum ◽

Excitatory Synapses ◽

Social Stimuli ◽

Aberrant Expression ◽

Behavioral Deficits ◽

Risk Gene ◽

Spectrum Disorders

AbstractNovel stimuli attract our attention, promote exploratory behavior, and facilitate learning. Atypical habituation and aberrant novelty exploration have been related with the severity of Autism Spectrum Disorders (ASD) but the underlying neuronal circuits are unknown. Here, we report that dopamine (DA) neurons of the ventral tegmental area (VTA) promote the behavioral responses to novel social stimuli, support preference for social novelty, and mediate the reinforcing properties of novel social interaction. Social novelty exploration is associated with the insertion of calcium-permeable GluA2-lacking AMPA-type glutamate receptors at excitatory synapses on VTA DA neurons. These novelty-dependent synaptic adaptations only persist upon repeated exposure to social stimuli and sustain social interaction. Global or DA neuron-specific inactivation of the ASD risk gene Neuroligin3 alters both social novelty exploration and the reinforcing properties of social stimuli. These behavioral deficits are accompanied by an aberrant expression of non-canonical GluA2-lacking AMPA-receptors at excitatory synapses on VTA DA neurons and an occlusion of novelty-induced synaptic plasticity. Altogether, these findings causally link impaired novelty exploration in an ASD mouse model to VTA DA circuit dysfunction.

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Calcium-Permeable Ampa Receptors are Absent in the Excitatory Synapses of Pyramidal Cells in Brain Tissue Obtained from Temporal Lobe Epilepsy Patients

Журнал эволюционной биохимии и физиологии ◽

10.31857/s0044452920072024 ◽

2020 ◽

Vol 56 (7) ◽

pp. 774-774

Author(s):

S. L. Malkin ◽

W. A. Khachatryan ◽

A. V. Zaitsev

Keyword(s):

Temporal Lobe Epilepsy ◽

Brain Tissue ◽

Temporal Lobe ◽

Ampa Receptors ◽

Pyramidal Cells ◽

Excitatory Synapses

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α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1524589113 ◽

2016 ◽

Vol 113 (19) ◽

pp. E2695-E2704 ◽

Cited By ~ 29

Author(s):

Mengping Wei ◽

Jian Zhang ◽

Moye Jia ◽

Chaojuan Yang ◽

Yunlong Pan ◽

...

Keyword(s):

Ampa Receptors ◽

Surface Expression ◽

Inhibitory Effect ◽

Synaptic Function ◽

Excitatory Synapses ◽

C Terminus ◽

Ampar Trafficking ◽

Excitatory Neurotransmission ◽

Induced Currents ◽

The Brain

In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/β-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6.

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AMPA and NMDA Receptors Expressed by Differentiating Xenopus Spinal Neurons

Journal of Neurophysiology ◽

10.1152/jn.1998.79.6.2986 ◽

1998 ◽

Vol 79 (6) ◽

pp. 2986-2998 ◽

Cited By ~ 29

Author(s):

Evanna L. Gleason ◽

Nicholas C. Spitzer

Keyword(s):

Nmda Receptors ◽

Glutamate Receptors ◽

Neuronal Differentiation ◽

Voltage Clamp ◽

Neural Development ◽

Ampa Receptors ◽

Reversal Potential ◽

Spinal Neurons ◽

Neurite Initiation ◽

Ampa And Nmda Receptors

Gleason, Evanna L. and Nicholas C. Spitzer. AMPA and NMDA receptors expressed by differentiating Xenopus spinal neurons. J. Neurophysiol. 79: 2986–2998, 1998. N-methyl-d-aspartate (NMDA) receptors are often the first ionotropic glutamate receptors expressed at early stages of development and appear to influence neuronal differentiation by mediating Ca2+ influx. Although less well studied, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors also can generate Ca2+ elevations and may have developmental roles. We document the presence of AMPA and NMDA class receptors and the absence of kainate class receptors with whole cell voltage-clamp recordings from Xenopus embryonic spinal neurons differentiated in vitro. Reversal potential measurements indicate that AMPA receptors are permeable to Ca2+ both in differentiated neurons and at the time they first are expressed. The P Ca/ P monocation of 1.9 is close to that of cloned Ca2+-permeable AMPA receptors expressed in heterologous systems. Ca2+ imaging reveals that Ca2+ elevations are elicited by AMPA or NMDA in the absence of Mg2+. The amplitudes and durations of these agonist-induced Ca2+ elevations are similar to those of spontaneous Ca2+ transients known to act as differentiation signals in these cells. Two sources of Ca2+ amplify AMPA- and NMDA-induced Ca2+ elevations. Activation of voltage-gated Ca2+ channels by AMPA- or NMDA-mediated depolarization contributes ∼15 or 30% of cytosolic Ca2+ elevations, respectively. Activation of either class of receptor produces elevations of Ca2+ that elicit further release of Ca2+ from thapsigargin-sensitive but ryanodine-insensitive stores, contributing an additional ∼30% of Ca2+ elevations. Voltage-clamp recordings and Ca2+ imaging both show that these spinal neurons express functional AMPA receptors soon after neurite initiation and before expression of NMDA receptors. The Ca2+ permeability of AMPA receptors, their ability to generate significant elevations of [Ca2+]i, and their appearance before synapse formation position them to play roles in neural development. Spontaneous release of agonists from growth cones is detected with glutamate receptors in outside-out patches, suggesting that spinal neurons are early, nonsynaptic sources of glutamate that can influence neuronal differentiation in vivo.

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