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Neuron Dec 2023Various specialized structural/functional properties are considered essential for contextual memory encoding by hippocampal mossy fiber (MF) synapses. Although...
Various specialized structural/functional properties are considered essential for contextual memory encoding by hippocampal mossy fiber (MF) synapses. Although investigated to exquisite detail in model organisms, synapses, including MFs, have undergone minimal functional interrogation in humans. To determine the translational relevance of rodent findings, we evaluated MF properties within human tissue resected to treat epilepsy. Human MFs exhibit remarkably similar hallmark features to rodents, including AMPA receptor-dominated synapses with small contributions from NMDA and kainate receptors, large dynamic range with strong frequency facilitation, NMDA receptor-independent presynaptic long-term potentiation, and strong cyclic AMP (cAMP) sensitivity of release. Array tomography confirmed the evolutionary conservation of MF ultrastructure. The astonishing congruence of rodent and human MF core features argues that the basic MF properties delineated in animal models remain critical to human MF function. Finally, a selective deficit in GABAergic inhibitory tone onto human MF postsynaptic targets suggests that unrestrained detonator excitatory drive contributes to epileptic circuit hyperexcitability.
Topics: Animals; Humans; Mossy Fibers, Hippocampal; Synapses; Long-Term Potentiation; Signal Transduction
PubMed: 37776852
DOI: 10.1016/j.neuron.2023.09.005 -
International Journal of Molecular... Dec 2023Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory... (Review)
Review
Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory synaptic transmission in glutamatergic neurons. The number and subunit composition of AMPARs are fundamental to synaptic plasticity and the formation of entire neural networks. Accordingly, the insertion and functionalization of AMPARs at the postsynaptic membrane have become a core issue related to neural circuit formation and information processing in the central nervous system. In this review, we summarize current knowledge regarding the related mechanisms of AMPAR expression and trafficking. The proteins related to AMPAR trafficking are discussed in detail, including vesicle-related proteins, cytoskeletal proteins, synaptic proteins, and protein kinases. Furthermore, significant emphasis was placed on the pivotal role of the actin cytoskeleton, which spans throughout the entire transport process in AMPAR transport, indicating that the actin cytoskeleton may serve as a fundamental basis for AMPAR trafficking. Additionally, we summarize the proteases involved in AMPAR post-translational modifications. Moreover, we provide an overview of AMPAR transport and localization to the postsynaptic membrane. Understanding the assembly, trafficking, and dynamic synaptic expression mechanisms of AMPAR may provide valuable insights into the cognitive decline associated with neurodegenerative diseases.
Topics: Receptors, AMPA; Central Nervous System; Neurons; Cognition; Learning; Central Nervous System Depressants
PubMed: 38203282
DOI: 10.3390/ijms25010111 -
Molecular Psychiatry Mar 2024Recent and pioneering animal research has revealed the brain utilizes a variety of molecular, cellular, and network-level mechanisms used to forget memories in a process... (Review)
Review
Recent and pioneering animal research has revealed the brain utilizes a variety of molecular, cellular, and network-level mechanisms used to forget memories in a process referred to as "active forgetting". Active forgetting increases behavioral flexibility and removes irrelevant information. Individuals with impaired active forgetting mechanisms can experience intrusive memories, distressing thoughts, and unwanted impulses that occur in neuropsychiatric diseases. The current evidence indicates that active forgetting mechanisms degrade, or mask, molecular and cellular memory traces created in synaptic connections of "engram cells" that are specific for a given memory. Combined molecular genetic/behavioral studies using Drosophila have uncovered a complex system of cellular active-forgetting pathways within engram cells that is regulated by dopamine neurons and involves dopamine-nitric oxide co-transmission and reception, endoplasmic reticulum Ca signaling, and cytoskeletal remodeling machinery regulated by small GTPases. Some of these molecular cellular mechanisms have already been found to be conserved in mammals. Interestingly, some pathways independently regulate forgetting of distinct memory types and temporal phases, suggesting a multi-layering organization of forgetting systems. In mammals, active forgetting also involves modulation of memory trace synaptic strength by altering AMPA receptor trafficking. Furthermore, active-forgetting employs network level mechanisms wherein non-engram neurons, newly born-engram neurons, and glial cells regulate engram synapses in a state and experience dependent manner. Remarkably, there is evidence for potential coordination between the network and cellular level forgetting mechanisms. Finally, subjects with several neuropsychiatric diseases have been tested and shown to be impaired in active forgetting. Insights obtained from research on active forgetting in animal models will continue to enrich our understanding of the brain dysfunctions that occur in neuropsychiatric diseases.
PubMed: 38532011
DOI: 10.1038/s41380-024-02521-9 -
Frontiers in Oncology 2023Human malignant brain tumors such as gliomas are devastating due to the induction of cerebral edema and neurodegeneration. A major contributor to glioma-induced... (Review)
Review
Human malignant brain tumors such as gliomas are devastating due to the induction of cerebral edema and neurodegeneration. A major contributor to glioma-induced neurodegeneration has been identified as glutamate. Glutamate promotes cell growth and proliferation in variety of tumor types. Intriguently, glutamate is also an excitatory neurotransmitter and evokes neuronal cell death at high concentrations. Even though glutamate signaling at the receptor and its downstream effectors has been extensively investigated at the molecular level, there has been little insight into how glutamate enters the tumor microenvironment and impacts on metabolic equilibration until recently. Surprisingly, the 12 transmembrane spanning tranporter xCT (SLC7A11) appeared to be a major player in this process, mediating glutamate secretion and ferroptosis. Also, PPARγ is associated with ferroptosis in neurodegeneration, thereby destroying neurons and causing brain swelling. Although these data are intriguing, tumor-associated edema has so far been quoted as of vasogenic origin. Hence, glutamate and PPARγ biology in the process of glioma-induced brain swelling is conceptually challenging. By inhibiting xCT transporter or AMPA receptors in vivo, brain swelling and peritumoral alterations can be mitigated. This review sheds light on the role of glutamate in brain tumors presenting the conceptual challenge that xCT disruption causes ferroptosis activation in malignant brain tumors. Thus, interfering with glutamate takes center stage in forming the basis of a metabolic equilibration approach.
PubMed: 37554158
DOI: 10.3389/fonc.2023.1176038 -
The Journal of Headache and Pain Aug 2023There is increasing evidence from human and animal studies that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura and a trigger of...
BACKGROUND
There is increasing evidence from human and animal studies that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura and a trigger of migraine pain mechanisms. The mechanisms of initiation of CSD in the brain of migraineurs remain unknown, and the mechanisms of initiation of experimentally induced CSD in normally metabolizing brain tissue remain incompletely understood and controversial. Here, we investigated the mechanisms of CSD initiation by focal application of KCl in mouse cerebral cortex slices.
METHODS
High KCl puffs of increasing duration up to the threshold duration eliciting a CSD were applied on layer 2/3 whilst the membrane potential of a pyramidal neuron located very close to the site of KCl application and the intrinsic optic signal were simultaneously recorded. This was done before and after the application of a specific blocker of either NMDA or AMPA glutamate receptors (NMDARs, AMPARs) or voltage-gated Ca (Ca) channels. If the drug blocked CSD, stimuli up to 12-15 times the threshold were applied.
RESULTS
Blocking either NMDARs with MK-801 or Ca channels with Ni completely inhibited CSD initiation by both CSD threshold and largely suprathreshold KCl stimuli. Inhibiting AMPARs with NBQX was without effect on the CSD threshold and velocity. Analysis of the CSD subthreshold and threshold neuronal depolarizations in control conditions and in the presence of MK-801 or Ni revealed that the mechanism underlying ignition of CSD by a threshold stimulus (and not by a just subthreshold stimulus) is the Ca-dependent activation of a threshold level of NMDARs (and/or of channels whose opening depends on the latter). The delay of several seconds with which this occurs underlies the delay of CSD initiation relative to the rapid neuronal depolarization produced by KCl.
CONCLUSIONS
Both NMDARs and Ca channels are necessary for CSD initiation, which is not determined by the extracellular K or neuronal depolarization levels per se, but requires the Ca-dependent activation of a threshold level of NMDARs. This occurs with a delay of several seconds relative to the rapid depolarization produced by the KCl stimulus. Our data give insights into potential mechanisms of CSD initiation in migraine.
Topics: Mice; Animals; Humans; Cortical Spreading Depression; Dizocilpine Maleate; Migraine Disorders; Receptors, N-Methyl-D-Aspartate; Migraine with Aura
PubMed: 37553625
DOI: 10.1186/s10194-023-01643-9 -
European Journal of Medicinal Chemistry Feb 2024The neuropharmacological community has shown a strong interest in AMPA receptors as critical components of excitatory synaptic transmission during the last fifteen... (Review)
Review
The neuropharmacological community has shown a strong interest in AMPA receptors as critical components of excitatory synaptic transmission during the last fifteen years. AMPA receptors, members of the ionotropic glutamate receptor family, allow rapid excitatory neurotransmission in the brain. AMPA receptors, which are permeable to sodium and potassium ions, manage the bulk of the brain's rapid synaptic communications. This study thoroughly examines the recent developments in AMPA receptor regulation, focusing on a shift from single chemical illustrations to a more extensive investigation of underlying processes. The complex interplay of these modulators in modifying the function and structure of AMPA receptors is the main focus, providing insight into their influence on the speed of excitatory neurotransmission. This research emphasizes the potential of AMPA receptor modulation as a therapy for various neurological disorders such as epilepsy and Alzheimer's disease. Analyzing these regulators' sophisticated molecular details enhances our comprehension of neuropharmacology, representing a significant advancement in using AMPA receptors for treating intricate neurological conditions.
Topics: Humans; Receptors, AMPA; Synaptic Transmission; Brain; Epilepsy
PubMed: 38237342
DOI: 10.1016/j.ejmech.2024.116151 -
ELife Nov 2023
PubMed: 37943030
DOI: 10.7554/eLife.94305 -
Cell Reports Jul 2023Rare genetic variants in ANK2, which encodes ankyrin-B, are associated with neurodevelopmental disorders (NDDs); however, their pathogenesis is poorly understood. We...
Rare genetic variants in ANK2, which encodes ankyrin-B, are associated with neurodevelopmental disorders (NDDs); however, their pathogenesis is poorly understood. We find that mice with prenatal deletion in cortical excitatory neurons and oligodendrocytes (Ank2:Emx1-Cre), but not with adolescent deletion in forebrain excitatory neurons (Ank2:CaMKIIα-Cre), display severe spontaneous seizures, increased mortality, hyperactivity, and social deficits. Calcium imaging of cortical slices from Ank2:Emx1-Cre mice shows increased neuronal calcium event amplitude and frequency, along with network hyperexcitability and hypersynchrony. Quantitative proteomic analysis of cortical synaptic membranes reveals upregulation of dendritic spine plasticity-regulatory proteins and downregulation of intermediate filaments. Characterization of the ankyrin-B interactome identifies interactors associated with autism and epilepsy risk factors and synaptic proteins. The AMPA receptor antagonist, perampanel, restores cortical neuronal activity and partially rescues survival in Ank2:Emx1-Cre mice. Our findings suggest that synaptic proteome alterations resulting from Ank2 deletion impair neuronal activity and synchrony, leading to NDDs-related behavioral impairments.
Topics: Animals; Mice; Ankyrins; Calcium; Phenotype; Prosencephalon; Proteome; Proteomics; Seizures; Mice, Knockout
PubMed: 37428632
DOI: 10.1016/j.celrep.2023.112784 -
Frontiers in Neurology 2023Glutamate is the brain's main excitatory neurotransmitter. Glutamatergic neurons primarily compose basic neuronal networks, especially in the cortex. An imbalance of... (Review)
Review
Glutamate is the brain's main excitatory neurotransmitter. Glutamatergic neurons primarily compose basic neuronal networks, especially in the cortex. An imbalance of excitatory and inhibitory activities may result in epilepsy or other neurological and psychiatric conditions. Among glutamate receptors, AMPA receptors are the predominant mediator of glutamate-induced excitatory neurotransmission and dictate synaptic efficiency and plasticity by their numbers and/or properties. Therefore, they appear to be a major drug target for modulating several brain functions. Perampanel (PER) is a highly selective, noncompetitive AMPA antagonist approved in several countries worldwide for treating different types of seizures in various epileptic conditions. However, recent data show that PER can potentially address many other conditions within epilepsy and beyond. From this perspective, this review aims to examine the new preclinical and clinical studies-especially those produced from 2017 onwards-on AMPA antagonism and PER in conditions such as mesial temporal lobe epilepsy, idiopathic and genetic generalized epilepsy, brain tumor-related epilepsy, status epilepticus, rare epileptic syndromes, stroke, sleep, epilepsy-related migraine, cognitive impairment, autism, dementia, and other neurodegenerative diseases, as well as provide suggestions on future research agenda aimed at probing the possibility of treating these conditions with PER and/or other AMPA receptor antagonists.
PubMed: 37483446
DOI: 10.3389/fneur.2023.1182304 -
Biomolecules Nov 2023Two of the most prevalent neurodegenerative disorders (NDDs), Alzheimer's disease (AD) and Parkinson's disease (PD), present significant challenges to healthcare systems... (Review)
Review
Two of the most prevalent neurodegenerative disorders (NDDs), Alzheimer's disease (AD) and Parkinson's disease (PD), present significant challenges to healthcare systems worldwide. While the etiologies of AD and PD differ, both diseases share commonalities in synaptic dysfunction, thereby focusing attention on the role of neurotransmitters. The possible functions that platelets may play in neurodegenerative illnesses including PD and AD are becoming more acknowledged. In AD, platelets have been investigated for their ability to generate amyloid-ß (Aß) peptides, contributing to the formation of neurotoxic plaques. Moreover, platelets are considered biomarkers for early AD diagnosis. In PD, platelets have been studied for their involvement in oxidative stress and mitochondrial dysfunction, which are key factors in the disease's pathogenesis. Emerging research shows that platelets, which release glutamate upon activation, also play a role in these disorders. Decreased glutamate uptake in platelets has been observed in Alzheimer's and Parkinson's patients, pointing to a systemic dysfunction in glutamate handling. This paper aims to elucidate the critical role that glutamate receptors play in the pathophysiology of both AD and PD. Utilizing data from clinical trials, animal models, and cellular studies, we reviewed how glutamate receptors dysfunction contributes to neurodegenerative (ND) processes such as excitotoxicity, synaptic loss, and cognitive impairment. The paper also reviews all current medications including glutamate receptor antagonists for AD and PD, highlighting their mode of action and limitations. A deeper understanding of glutamate receptor involvement including its systemic regulation by platelets could open new avenues for more effective treatments, potentially slowing disease progression and improving patient outcomes.
Topics: Animals; Humans; Parkinson Disease; Alzheimer Disease; Glutamic Acid; Receptors, Glutamate
PubMed: 38002291
DOI: 10.3390/biom13111609