Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

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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Cul4 ubiquitin ligase cofactor DCAF12 promotes neurotransmitter release and homeostatic plasticity

The Journal of Cell Biology ◽

10.1083/jcb.201805099 ◽

2019 ◽

Vol 218 (3) ◽

pp. 993-1010 ◽

Cited By ~ 3

Author(s):

Lilian A. Patrón ◽

Kei Nagatomo ◽

David Tyler Eves ◽

Mays Imad ◽

Kimberly Young ◽

...

Keyword(s):

Glutamate Receptor ◽

Motor Neurons ◽

Ubiquitin Ligase ◽

Neurotransmitter Release ◽

Neuromuscular Junctions ◽

Synaptic Function ◽

Homeostatic Plasticity ◽

Independent Functions ◽

Synaptic Boutons

We genetically characterized the synaptic role of the Drosophila homologue of human DCAF12, a putative cofactor of Cullin4 (Cul4) ubiquitin ligase complexes. Deletion of Drosophila DCAF12 impairs larval locomotion and arrests development. At larval neuromuscular junctions (NMJs), DCAF12 is expressed presynaptically in synaptic boutons, axons, and nuclei of motor neurons. Postsynaptically, DCAF12 is expressed in muscle nuclei and facilitates Cul4-dependent ubiquitination. Genetic experiments identified several mechanistically independent functions of DCAF12 at larval NMJs. First, presynaptic DCAF12 promotes evoked neurotransmitter release. Second, postsynaptic DCAF12 negatively controls the synaptic levels of the glutamate receptor subunits GluRIIA, GluRIIC, and GluRIID. The down-regulation of synaptic GluRIIA subunits by nuclear DCAF12 requires Cul4. Third, presynaptic DCAF12 is required for the expression of synaptic homeostatic potentiation. We suggest that DCAF12 and Cul4 are critical for normal synaptic function and plasticity at larval NMJs.

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LGI1–ADAM22–MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2022580118 ◽

2021 ◽

Vol 118 (3) ◽

pp. e2022580118

Author(s):

Yuko Fukata ◽

Xiumin Chen ◽

Satomi Chiken ◽

Yoko Hirano ◽

Atsushi Yamagata ◽

...

Keyword(s):

Synaptic Transmission ◽

Ampa Receptors ◽

Neurotransmitter Release ◽

Epileptic Encephalopathy ◽

Secreted Protein ◽

Gene Products ◽

Molecular Identity ◽

Postsynaptic Receptors ◽

Epilepsy Gene ◽

The Brain

Physiological functioning and homeostasis of the brain rely on finely tuned synaptic transmission, which involves nanoscale alignment between presynaptic neurotransmitter-release machinery and postsynaptic receptors. However, the molecular identity and physiological significance of transsynaptic nanoalignment remain incompletely understood. Here, we report that epilepsy gene products, a secreted protein LGI1 and its receptor ADAM22, govern transsynaptic nanoalignment to prevent epilepsy. We found that LGI1–ADAM22 instructs PSD-95 family membrane-associated guanylate kinases (MAGUKs) to organize transsynaptic protein networks, including NMDA/AMPA receptors, Kv1 channels, and LRRTM4–Neurexin adhesion molecules. Adam22ΔC5/ΔC5 knock-in mice devoid of the ADAM22–MAGUK interaction display lethal epilepsy of hippocampal origin, representing the mouse model for ADAM22-related epileptic encephalopathy. This model shows less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission in the hippocampus. Strikingly, without ADAM22 binding, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Furthermore, forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in nonneuronal cells. Collectively, this study reveals LGI1–ADAM22–MAGUK as an essential component of transsynaptic nanoarchitecture for precise synaptic transmission and epilepsy prevention.

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Reelin restricts dendritic growth of interneurons in the neocortex

Development ◽

10.1242/dev.199718 ◽

2021 ◽

Vol 148 (17) ◽

Author(s):

Mohammad I. K. Hamad ◽

Petya Petrova ◽

Solieman Daoud ◽

Obada Rabaya ◽

Abdalrahim Jbara ◽

...

Keyword(s):

Neuropeptide Y ◽

Ampa Receptors ◽

Neuronal Migration ◽

Neurotransmitter Release ◽

Dendritic Growth ◽

Embryonic Brain ◽

Retzius Cells ◽

Ca2 Channels ◽

Interneuron Development

ABSTRACT Reelin is a large secreted glycoprotein that regulates neuronal migration, lamination and establishment of dendritic architecture in the embryonic brain. Reelin expression switches postnatally from Cajal-Retzius cells to interneurons. However, reelin function in interneuron development is still poorly understood. Here, we have investigated the role of reelin in interneuron development in the postnatal neocortex. To preclude early cortical migration defects caused by reelin deficiency, we employed a conditional reelin knockout (RelncKO) mouse to induce postnatal reelin deficiency. Induced reelin deficiency caused dendritic hypertrophy in distal dendritic segments of neuropeptide Y-positive (NPY+) and calretinin-positive (Calr+) interneurons, and in proximal dendritic segments of parvalbumin-positive (Parv+) interneurons. Chronic recombinant Reelin treatment rescued dendritic hypertrophy in Relncko interneurons. Moreover, we provide evidence that RelncKO interneuron hypertrophy is due to presynaptic GABABR dysfunction. Thus, GABABRs in RelncKO interneurons were unable to block N-type (Cav2.2) Ca2+ channels that control neurotransmitter release. Consequently, the excessive Ca2+ influx through AMPA receptors, but not NMDA receptors, caused interneuron dendritic hypertrophy. These findings suggest that reelin acts as a ‘stop-growth-signal’ for postnatal interneuron maturation.

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Copper Inhibits NMDA Receptor-Independent LTP and Modulates the Paired-Pulse Ratio after LTP in Mouse Hippocampal Slices

International Journal of Alzheimer s Disease ◽

10.4061/2011/864753 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 13

Author(s):

Nina L. Salazar-Weber ◽

Jeffrey P. Smith

Keyword(s):

Nmda Receptor ◽

Ampa Receptors ◽

Neurotransmitter Release ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Dependent Manner ◽

Paired Pulse ◽

Pulse Ratio ◽

Term Potentiation

Copper misregulation has been implicated in the pathological processes underlying deterioration of learning and memory in Alzheimer's disease and other neurodegenerative disorders. Supporting this, inhibition of long-term potentiation (LTP) by copper (II) has been well established, but the exact mechanism is poorly characterized. It is thought that an interaction between copper and postsynaptic NMDA receptors is a major part of the mechanism; however, in this study, we found that copper (II) inhibited NMDA receptor-independent LTP in the CA3 region of hippocampal slices. In addition, in the CA3 and CA1 regions, copper modulated the paired-pulse ratio (PPR) in an LTP-dependent manner. Combined, this suggests the involvement of a presynaptic mechanism in the modulation of synaptic plasticity by copper. Inhibition of the copper-dependent changes in the PPR with cyclothiazide suggested that this may involve an interaction with the presynaptic AMPA receptors that regulate neurotransmitter release.

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Postsynaptic neuroligin-1 mediates presynaptic endocytosis during neuronal activity

10.1101/2021.07.20.453031 ◽

2021 ◽

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 (Nlgn-1) 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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Properties of GABAergic Neurons Containing Calcium-Permeable Kainate and AMPA-Receptors

Life ◽

10.3390/life11121309 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1309

Author(s):

Valery Petrovich Zinchenko ◽

Artem Mikhailovich Kosenkov ◽

Sergei Gennadevich Gaidin ◽

Alexander Igorevich Sergeev ◽

Ludmila Petrovna Dolgacheva ◽

...

Keyword(s):

Ampa Receptors ◽

Neurotransmitter Release ◽

Domoic Acid ◽

Gaba Release ◽

Gabaergic Neurons ◽

Pivotal Role ◽

Inhibitory Neurons ◽

Glutamatergic Neurons ◽

Selective Agonist ◽

First Time

Calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs), as well as NMDARs, play a pivotal role in plasticity and in regulating neurotransmitter release. Here we visualized in the mature hippocampal neuroglial cultures the neurons expressing CP-AMPARs and CP-KARs. These neurons were visualized by a characteristic fast sustained [Ca2+]i increase in response to the agonist of these receptors, domoic acid (DoA), and a selective agonist of GluK1-containing KARs, ATPA. Neurons from both subpopulations are GABAergic. The subpopulation of neurons expressing CP-AMPARs includes a larger percentage of calbindin-positive neurons (39.4 ± 6.0%) than the subpopulation of neurons expressing CP-KARs (14.2 ± 7.5% of CB+ neurons). In addition, we have shown for the first time that NH4Cl-induced depolarization faster induces an [Ca2+]i elevation in GABAergic neurons expressing CP-KARs and CP-AMPARs than in most glutamatergic neurons. CP-AMPARs antagonist, NASPM, increased the amplitude of the DoA-induced Ca2+ response in GABAergic neurons expressing CP-KARs, indicating that neurons expressing CP-AMPARs innervate GABAergic neurons expressing CP-KARs. We assume that CP-KARs in inhibitory neurons are involved in the mechanism of outstripping GABA release upon hyperexcitation.

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