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BioRxiv : the Preprint Server For... Nov 2023Excitatory neurotransmission is principally mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). Dysregulation of AMPARs is the cause of many neurological...
Excitatory neurotransmission is principally mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). Dysregulation of AMPARs is the cause of many neurological disorders and how therapeutic candidates such as negative allosteric modulators inhibit AMPARs is unclear. Here, we show that non-competitive inhibition desensitizes AMPARs to activation and prevents positive allosteric modulation. We dissected the noncompetitive inhibition mechanism of action by capturing AMPARs bound to glutamate and the prototypical negative allosteric modulator, GYKI-52466, with cryo-electron microscopy. Noncompetitive inhibition by GYKI-52466, which binds in the transmembrane collar region surrounding the ion channel, negatively modulates AMPARs by decoupling glutamate binding in the ligand binding domain from the ion channel. Furthermore, during allosteric competition between negative and positive modulators, negative allosteric modulation by GKYI-52466 outcompetes positive allosteric modulators to control AMPAR function. Our data provide a new framework for understanding allostery of AMPARs and foundations for rational design of therapeutics targeting AMPARs in neurological diseases.
PubMed: 38076818
DOI: 10.1101/2023.11.28.569057 -
Cellular and Molecular Life Sciences :... Nov 2023AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus,...
AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus, their functional characteristics are a critical determinant of brain function. We evaluate intolerance of each GRIA gene to genetic variation using 3DMTR and report here the functional consequences of 52 missense variants in GRIA1-4 identified in patients with various neurological disorders. These variants produce changes in agonist EC, response time course, desensitization, and/or receptor surface expression. We predict that these functional and localization changes will have important consequences for circuit function, and therefore likely contribute to the patients' clinical phenotype. We evaluated the sensitivity of variant receptors to AMPAR-selective modulators including FDA-approved drugs to explore potential targeted therapeutic options.
Topics: Humans; Nervous System Diseases; Synaptic Transmission; Receptors, AMPA; Synapses
PubMed: 37921875
DOI: 10.1007/s00018-023-04991-6 -
Proceedings of the National Academy of... Oct 2023AMPA receptors (AMPARs) play a critical role in synaptic plasticity and learning and memory, and dysfunction or dysregulation of AMPARs could lead to various...
AMPA receptors (AMPARs) play a critical role in synaptic plasticity and learning and memory, and dysfunction or dysregulation of AMPARs could lead to various neurological and psychiatric disorders, such as Alzheimer's disease (AD). However, the dynamics and/or longitudinal changes of AMPARs in vivo during AD pathogenesis remain elusive. Here, employing 5xFAD SEP-GluA1 KI mice, we investigated endogenous AMPA receptor dynamics in a whisker deflection-associated Go/No-go learning paradigm. We found a significant increase in synaptosomal AMPA receptor subunits GluA1 in WT mice after learning, while no such changes were detected in 7-mo-old 5xFAD mice. Daily training led to an increase in endogenous spine surface GluA1 in Control mice, while this increase was absent in 5xFAD-KI mice which correlates with its learning defects in Go/No-go paradigm. Furthermore, we demonstrated that the onset of abnormal AMPAR dynamics corresponds temporally with microglia and astrocyte overactivation. Our results have shown that impairments in endogenous AMPA receptor dynamics play an important role in learning deficits in 5xFAD mice and AD pathogenesis.
Topics: Humans; Animals; Mice; Receptors, AMPA; Alzheimer Disease; Learning; Astrocytes; Microglia
PubMed: 37748061
DOI: 10.1073/pnas.2303878120 -
Glia Sep 2023The pro-inflammatory cytokine tumor necrosis factor α (TNFα) tunes the capacity of neurons to express synaptic plasticity. It remains, however, unclear how TNFα...
The pro-inflammatory cytokine tumor necrosis factor α (TNFα) tunes the capacity of neurons to express synaptic plasticity. It remains, however, unclear how TNFα mediates synaptic positive (=change) and negative (=stability) feedback mechanisms. We assessed effects of TNFα on microglia activation and synaptic transmission onto CA1 pyramidal neurons of mouse organotypic entorhino-hippocampal tissue cultures. TNFα mediated changes in excitatory and inhibitory neurotransmission in a concentration-dependent manner, where low concentration strengthened glutamatergic neurotransmission via synaptic accumulation of GluA1-only-containing AMPA receptors and higher concentration increased inhibition. The latter induced the synaptic accumulation of GluA1-only-containing AMPA receptors as well. However, activated, pro-inflammatory microglia mediated a homeostatic adjustment of excitatory synapses, that is, an initial increase in excitatory synaptic strength at 3 h returned to baseline within 24 h, while inhibitory neurotransmission increased. In microglia-depleted tissue cultures, synaptic strengthening triggered by high levels of TNFα persisted and the impact of TNFα on inhibitory neurotransmission was still observed and dependent on its concentration. These findings underscore the essential role of microglia in TNFα-mediated synaptic plasticity. They suggest that pro-inflammatory microglia mediate synaptic homeostasis, that is, negative feedback mechanisms, which may affect the ability of neurons to express further plasticity, thereby emphasizing the importance of microglia as gatekeepers of synaptic change and stability.
Topics: Mice; Animals; Tumor Necrosis Factor-alpha; Microglia; Receptors, AMPA; Neuronal Plasticity; Hippocampus; Synaptic Transmission; Synapses
PubMed: 37208965
DOI: 10.1002/glia.24383 -
Brain Sciences Oct 2023Reelin is an extracellular matrix glycoprotein involved in neuronal migration during embryonic brain development and synaptic plasticity in the adult brain. The role of... (Review)
Review
Reelin is an extracellular matrix glycoprotein involved in neuronal migration during embryonic brain development and synaptic plasticity in the adult brain. The role of Reelin in the developing central nervous system has been extensively characterized. Indeed, a loss of Reelin or a disruption in its signaling cascade leads to neurodevelopmental defects and is associated with ataxia, intellectual disability, autism, and several psychiatric disorders. In the adult brain, Reelin is critically involved in neurogenesis and synaptic plasticity. Reelin's signaling potentiates glutamatergic and GABAergic neurotransmission, induces synaptic maturation, and increases AMPA and NMDA receptor subunits' expression and activity. As a result, there is a growing literature reporting that a loss of function and/or reduction of Reelin is implicated in numerous neurodegenerative diseases. The present review summarizes the current state of the literature regarding the implication of Reelin and Reelin-mediated signaling during aging and neurodegenerative disorders, highlighting Reelin as a possible target in the prevention or treatment of progressive neurodegeneration.
PubMed: 37891846
DOI: 10.3390/brainsci13101479 -
Nature Communications Oct 2023Transmembrane AMPA receptor regulatory proteins (TARPs) and germ cell-specific gene 1-like protein (GSG1L) are claudin-type AMPA receptor (AMPAR) auxiliary subunits that...
Transmembrane AMPA receptor regulatory proteins (TARPs) and germ cell-specific gene 1-like protein (GSG1L) are claudin-type AMPA receptor (AMPAR) auxiliary subunits that profoundly regulate glutamatergic synapse strength and plasticity. While AMPAR-TARP complexes have been extensively studied, less is known about GSG1L-containing AMPARs. Here, we show that GSG1L's spatiotemporal expression, native interactome and allosteric sites are distinct. GSG1L generally expresses late during brain development in a region-specific manner, constituting about 5% of all AMPAR complexes in adulthood. While GSG1L can co-assemble with TARPs or cornichons (CNIHs), it also assembles as the sole auxiliary subunit. Unexpectedly, GSG1L acts through two discrete evolutionarily-conserved sites on the agonist-binding domain with a weak allosteric interaction at the TARP/KGK site to slow desensitization, and a stronger interaction at a different site that slows recovery from desensitization. Together, these distinctions help explain GSG1L's evolutionary past and how it fulfills a unique signaling role within glutamatergic synapses.
Topics: Receptors, AMPA; Allosteric Site; Proteins; Synapses
PubMed: 37884493
DOI: 10.1038/s41467-023-42517-7 -
Naunyn-Schmiedeberg's Archives of... Dec 2023The present study evaluates the effect of modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) by inhibiting them in the acute phase and...
The present study evaluates the effect of modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) by inhibiting them in the acute phase and activating them in the sub-acute phase on post-stroke recovery in middle cerebral artery occlusion (MCAo) model of stroke in rats. After 90 min of MCAo, perampanel (an AMPAR antagonist, 1.5 mg/kg i.p) and aniracetam (an AMPA agonist, 50 mg/kg i.p.) were administered for different durations after MCAo. Later, after obtaining the best time point for the antagonist and the agonist treatment protocols, sequential treatment with perampanel and aniracetam were given, and the effect on neurological damage and post stroke recovery were assessed. Perampanel and aniracetam significantly protected MCAo-induced neurological damage and diminished the infarct percentage. Furthermore, treatment with these study drugs improved the motor coordination and grip strength. Sequential treatment with perampanel and aniracetam reduced the infarct percentage as assessed by MRI. Moreover, these compounds diminished the inflammation via reducing the levels of pro-inflammatory cytokines (TNF-α, IL-1β) and increasing the levels of anti-inflammatory cytokine (IL-10) along with reductions in GFAP expression. Moreover, the neuroprotective markers (BDNF and TrkB) were found to be significantly increased. Levels of apoptotic markers (Bax, cleaved-caspase-3; Bcl2 and TUNEL positive cells) and neuronal damage (MAP-2) were normalized with the AMPA antagonist and agonist treatment. Expressions of GluR1 and GluR2 subunits of AMPAR were significantly enhanced with sequential treatment. The present study thus showed that modulation of AMPAR improves neurobehavioral deficits and reduces the infarct percentage through anti-inflammatory, neuroprotective and anti-apoptotic effects.
Topics: Rats; Animals; Receptors, AMPA; Ischemic Stroke; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Stroke; Infarction, Middle Cerebral Artery; Anti-Inflammatory Agents; Models, Theoretical; Neuroprotective Agents
PubMed: 37231168
DOI: 10.1007/s00210-023-02544-z -
Current Neuropharmacology Sep 2023The mechanisms underlying the action of lithium (LiCl) in bipolar disorder(BD) are still far from being completely understood. Previous evidence has revealed that BD is...
BACKGROUND
The mechanisms underlying the action of lithium (LiCl) in bipolar disorder(BD) are still far from being completely understood. Previous evidence has revealed that BD is characterized by glutamate hyperexcitability, suggesting that LiCl may act, at least partially, by toning down glutamatergic signaling abnormalities.
OBJECTIVE
In this study, taking advantage of western blot and confocal microscopy, we used a combination of integrative molecular and morphological approaches in rats exposed to repeated administration of LiCl at a therapeutic dose (between 0.6 and 1.2 mmol/l) and sacrificed at two different time points, i.e., 24 hours and 7 days after the last exposure.
RESULTS
We report that repeated LiCl treatment activates multiple, parallel, but also converging forms of compensatory neuroplasticity related to glutamatergic signaling. More specifically, LiCl promoted a wave of neuroplasticity in the hippocampus, involving the synaptic recruitment of GluN2A-containing NMDA receptors, GluA1-containing AMPA receptors, and the neurotrophin BDNF that are indicative of a more plastic spine. The latter is evidenced by morphological analyses showing changes in dendritic spine morphology, such as increased length and head diameter of such spines. These changes may counteract the potentially negative extra-synaptic movements of GluN2B-containing NMDA receptors as well as the increase in the formation of GluA2-lacking Ca2+-permeable AMPA receptors.
CONCLUSION
Our findings highlight a previously unknown cohesive picture of the glutamatergic implications of LiCl action that persist long after the end of its administration, revealing for the first time a profound and persistent reorganization of the glutamatergic postsynaptic density receptor composition and structure.
PubMed: 37711124
DOI: 10.2174/1570159X21666230913144420 -
Progress in Neurobiology Dec 2023Repeated generalized tonic-clonic seizures (GTCSs) are the most critical risk factor for sudden unexpected death in epilepsy (SUDEP). GTCSs can cause fatal apnea. We...
Repeated generalized tonic-clonic seizures (GTCSs) are the most critical risk factor for sudden unexpected death in epilepsy (SUDEP). GTCSs can cause fatal apnea. We investigated neuronal plasticity mechanisms that precipitate postictal apnea and seizure-induced death. Repeated seizures worsened behavior, precipitated apnea, and enlarged active neuronal circuits, recruiting more neurons in such brainstem nuclei as periaqueductal gray (PAG) and dorsal raphe, indicative of brainstem plasticity. Seizure-activated neurons are more excitable and have enhanced AMPA-mediated excitatory transmission after a seizure. Global deletion of the GluA1 subunit of AMPA receptors abolishes postictal apnea and seizure-induced death. Treatment with a drug that blocks Ca-permeable AMPA receptors also renders mice apnea-free with five-fold better survival than untreated mice. Repeated seizures traffic the GluA1 subunit-containing AMPA receptors to synapses, and blocking this mechanism decreases the probability of postictal apnea and seizure-induced death.
Topics: Mice; Animals; Apnea; Receptors, AMPA; Seizures; Brain Stem; Risk Factors
PubMed: 37778436
DOI: 10.1016/j.pneurobio.2023.102531