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Cell Reports Oct 2023Chronic pain is a complex experience with multifaceted behavioral manifestations, often leading to pain avoidance at the expense of reward approach. How pain facilitates...
Chronic pain is a complex experience with multifaceted behavioral manifestations, often leading to pain avoidance at the expense of reward approach. How pain facilitates avoidance in situations with mixed outcomes is unknown. The anterior cingulate cortex (ACC) plays a key role in pain processing and in value-based decision-making. Distinct ACC inputs inform about the sensory and emotional quality of pain. However, whether specific ACC circuits underlie pathological conflict assessment in pain remains underexplored. Here, we demonstrate that mice with chronic pain favor cold avoidance rather than reward approach in a conflicting task. This occurs along with selective strengthening of basolateral amygdala inputs onto ACC layer 2/3 pyramidal neurons. The amygdala-cingulate projection is necessary and sufficient for the conflicting cold avoidance. Further, low-frequency stimulation of this pathway restores AMPA receptor function and reduces avoidance in pain mice. Our findings provide insights into the circuits and mechanisms underlying cognitive aspects of pain and offer potential targets for treatment.
Topics: Mice; Animals; Gyrus Cinguli; Chronic Pain; Amygdala; Basolateral Nuclear Complex; Emotions
PubMed: 37733589
DOI: 10.1016/j.celrep.2023.113125 -
Neuron Feb 2024
PubMed: 38330900
DOI: 10.1016/j.neuron.2024.01.012 -
Science Advances Dec 2023While most research and treatments for multiple sclerosis (MS) focus on autoimmune reactions causing demyelination, it is possible that neurodegeneration precedes the...
While most research and treatments for multiple sclerosis (MS) focus on autoimmune reactions causing demyelination, it is possible that neurodegeneration precedes the autoimmune response. Hence, glutamate receptor antagonists preventing excitotoxicity showed promise in MS animal models, though blocking glutamate signaling prevents critical neuronal functions. This study reports the discovery of a small molecule that prevents AMPA-mediated excitotoxicity by targeting an allosteric binding site. A machine learning approach was used to screen for small molecules targeting the AMPA receptor GluA2 subunit. The lead candidate has potent effects in restoring neurological function and myelination while reducing the immune response in experimental autoimmune encephalitis and cuprizone MS mouse models without affecting basal neurotransmission or learning and memory. These findings facilitate development of a treatment for MS with a different mechanism of action than current immune modulatory drugs and avoids important off-target effects of glutamate receptor antagonists. This class of MS therapeutics could be useful as an alternative or complementary treatment to existing therapies.
Topics: Mice; Animals; Multiple Sclerosis; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Excitatory Amino Acid Antagonists; Receptors, AMPA; Neurons
PubMed: 38064562
DOI: 10.1126/sciadv.adj6187 -
International Journal of Molecular... Oct 2023Autoantibodies against NMDA and AMPA receptors have been identified in the central nervous system of patients suffering from brain disorders characterized by... (Review)
Review
Autoantibodies against NMDA and AMPA receptors have been identified in the central nervous system of patients suffering from brain disorders characterized by neurological and psychiatric symptoms. It has been demonstrated that these autoantibodies can affect the functions and/or the expression of the targeted receptors, altering synaptic communication. The importance to clarify, in preclinical models, the molecular mechanisms involved in the autoantibody-mediated effects has emerged in order to understand their pathogenic role in central disorders, but also to propose new therapeutic approaches for preventing the deleterious central consequences. In this review, we describe some of the available preclinical literature concerning the impact of antibodies recognizing NMDA and AMPA receptors in neurons. This review discusses the cellular events that would support the detrimental roles of the autoantibodies, also illustrating some contrasting findings that in our opinion deserve attention and further investigations before translating the preclinical observations to clinic.
Topics: Humans; Receptors, AMPA; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Neurons; Autoantibodies
PubMed: 37834353
DOI: 10.3390/ijms241914905 -
Communications Biology Dec 2023The brain consists of the left and right cerebral hemispheres and both are connected by callosal projections. Less is known about the basic mechanism of this...
The brain consists of the left and right cerebral hemispheres and both are connected by callosal projections. Less is known about the basic mechanism of this cortical-cortical connection and its functional importance. Here we investigate the cortical-cortical connection between the bilateral anterior cingulate cortex (ACC) by using the classic electrophysiological and optogenetic approach. We find that there is a direct synaptic projection from one side ACC to the contralateral ACC. Glutamate is the major excitatory transmitter for bilateral ACC connection, including projections to pyramidal cells in superficial (II/III) and deep (V/VI) layers of the ACC. Both AMPA and kainate receptors contribute to synaptic transmission. Repetitive stimulation of the projection also evoked postsynaptic Ca influx in contralateral ACC pyramidal neurons. Behaviorally, light activation of the ACC-ACC connection facilitated behavioral withdrawal responses to mechanical stimuli and noxious heat. In an animal model of neuropathic pain, light inhibitory of ACC-ACC connection reduces both primary and secondary hyperalgesia. Our findings provide strong direct evidence for the excitatory or facilitatory contribution of ACC-ACC connection to pain perception, and this mechanism may provide therapeutic targets for future treatment of chronic pain and related emotional disorders.
Topics: Mice; Animals; Gyrus Cinguli; Synaptic Transmission; Neuralgia; Pyramidal Cells; Glutamic Acid
PubMed: 38071375
DOI: 10.1038/s42003-023-05589-1 -
Protein Science : a Publication of the... Nov 2023The human flavoenzyme D-aspartate oxidase (hDASPO) controls the level of D-aspartate in the brain, a molecule acting as an agonist of NMDA receptors and modulator of...
The human flavoenzyme D-aspartate oxidase (hDASPO) controls the level of D-aspartate in the brain, a molecule acting as an agonist of NMDA receptors and modulator of AMPA and mGlu5 receptors. hDASPO-induced D-aspartate degradation prevents age-dependent deterioration of brain functions and is related to psychiatric disorders such as schizophrenia and autism. Notwithstanding this crucial role, less is known about hDASPO regulation. Here, we report that hDASPO is nitrosylated in vitro, while no evidence of sulfhydration and phosphorylation is apparent: nitrosylation affects the activity of the human flavoenzyme to a limited extent. Furthermore, hDASPO interacts with the primate-specific protein pLG72 (a well-known negative chaperone of D-amino acid oxidase, the enzyme deputed to D-serine degradation in the human brain), yielding a ~114 kDa complex, with a micromolar dissociation constant, promoting the flavoenzyme inactivation. At the cellular level, pLG72 and hDASPO generate a cytosolic complex: the expression of pLG72 negatively affects the hDASPO level by reducing its half-life. We propose that pLG72 binding may represent a protective mechanism aimed at avoiding cytotoxicity due to H O produced by the hDASPO enzymatic degradation of D-aspartate, especially before the final targeting to peroxisomes.
Topics: Animals; Humans; Oxidoreductases; D-Aspartate Oxidase; D-Aspartic Acid; Schizophrenia; Carrier Proteins
PubMed: 37805834
DOI: 10.1002/pro.4802 -
Neuron Aug 2023Information processing and storage in the brain rely on AMPA-receptors (AMPARs) and their context-dependent dynamics in synapses and extra-synaptic sites. We found that...
Information processing and storage in the brain rely on AMPA-receptors (AMPARs) and their context-dependent dynamics in synapses and extra-synaptic sites. We found that distribution and dynamics of AMPARs in the plasma membrane are controlled by Noelins, a three-member family of conserved secreted proteins expressed throughout the brain in a cell-type-specific manner. Noelin tetramers tightly assemble with the extracellular domains of AMPARs and interconnect them in a network-like configuration with a variety of secreted and membrane-anchored proteins including Neurexin1, Neuritin1, and Seizure 6-like. Knock out of Noelins1-3 profoundly reduced AMPARs in synapses onto excitatory and inhibitory (inter)neurons, decreased their density and clustering in dendrites, and abolished activity-dependent synaptic plasticity. Our results uncover an endogenous mechanism for extracellular anchoring of AMPARs and establish Noelin-organized networks as versatile determinants of constitutive and context-dependent neurotransmission.
Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Membrane Proteins; Biological Transport; Brain; Cell Membrane; Receptors, AMPA
PubMed: 37591201
DOI: 10.1016/j.neuron.2023.07.013 -
European Journal of Pharmacology Sep 2023Prenatal alcohol exposure (PAE) affects neuronal networks and brain development causing a range of physical, cognitive and behavioural disorders in newborns that persist...
Prenatal alcohol exposure (PAE) affects neuronal networks and brain development causing a range of physical, cognitive and behavioural disorders in newborns that persist into adulthood. The array of consequences associated with PAE can be grouped under the umbrella-term 'fetal alcohol spectrum disorders' (FASD). Unfortunately, there is no cure for FASD as the molecular mechanisms underlying this pathology are still unknown. We have recently demonstrated that chronic EtOH exposure, followed by withdrawal, induces a significant decrease in AMPA receptor (AMPAR) expression and function in developing hippocampus in vitro. Here, we explored the EtOH-dependent pathways leading to hippocampal AMPAR suppression. Organotypic hippocampal slices (2 days in cultures) were exposed to EtOH (150 mM) for 7 days followed by 24 h EtOH withdrawal. Then, the slices were analysed by means of RT-PCR for miRNA content, western blotting for AMPA and NMDA related-synaptic proteins expression in postsynaptic compartment and electrophysiology to record electrical properties from CA1 pyramidal neurons. We observed that EtOH induces a significant downregulation of postsynaptic AMPA and NMDA subunits and relative scaffolding protein expression and, accordingly, a decrease of AMPA-mediated neurotransmission. Simultaneously, we found that chronic EtOH induced-upregulation of miRNA 137 and 501-3p and decreased AMPA-mediated neurotransmission are prevented by application of the selective mGlu5 antagonist MPEP during EtOH withdrawal. Our data indicate mGlu5 via miRNA137 and 501-3p expression as key factors in the regulation of AMPAergic neurotransmission that may contribute, at least in part, to the pathogenesis of FASD.
Topics: Infant, Newborn; Humans; Female; Pregnancy; Ethanol; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; N-Methylaspartate; Up-Regulation; Fetal Alcohol Spectrum Disorders; Receptors, N-Methyl-D-Aspartate; Prenatal Exposure Delayed Effects; Hippocampus; Receptors, AMPA; MicroRNAs
PubMed: 37433363
DOI: 10.1016/j.ejphar.2023.175878 -
Molecular Neurodegeneration Sep 2023RNA editing at the Q/R site of GluA2 occurs with ~99% efficiency in the healthy brain, so that the majority of AMPARs contain GluA2(R) instead of the exonically encoded...
The Q/R editing site of AMPA receptor GluA2 subunit acts as an epigenetic switch regulating dendritic spines, neurodegeneration and cognitive deficits in Alzheimer's disease.
BACKGROUND
RNA editing at the Q/R site of GluA2 occurs with ~99% efficiency in the healthy brain, so that the majority of AMPARs contain GluA2(R) instead of the exonically encoded GluA2(Q). Reduced Q/R site editing infcreases AMPA receptor calcium permeability and leads to dendritic spine loss, neurodegeneration, seizures and learning impairments. Furthermore, GluA2 Q/R site editing is impaired in Alzheimer's disease (AD), raising the possibility that unedited GluA2(Q)-containing AMPARs contribute to synapse loss and neurodegeneration in AD. If true, then inhibiting expression of unedited GluA2(Q), while maintaining expression of GluA2(R), may be a novel strategy of preventing synapse loss and neurodegeneration in AD.
METHODS
We engineered mice with the 'edited' arginine codon (CGG) in place of the unedited glutamine codon (CAG) at position 607 of the Gria2 gene. We crossbred this line with the J20 mouse model of AD and conducted anatomical, electrophysiological and behavioural assays to determine the impact of eliminating unedited GluA2(Q) expression on AD-related phenotypes.
RESULTS
Eliminating unedited GluA2(Q) expression in AD mice prevented dendritic spine loss and hippocampal CA1 neurodegeneration as well as improved working and reference memory in the radial arm maze. These phenotypes were improved independently of Aβ pathology and ongoing seizure susceptibility. Surprisingly, our data also revealed increased spine density in non-AD mice with exonically encoded GluA2(R) as compared to their wild-type littermates, suggesting an unexpected and previously unknown role for unedited GluA2(Q) in regulating dendritic spines.
CONCLUSION
The Q/R editing site of the AMPA receptor subunit GluA2 may act as an epigenetic switch that regulates dendritic spines, neurodegeneration and memory deficits in AD.
Topics: Animals; Mice; Dendritic Spines; Receptors, AMPA; Alzheimer Disease; Epigenesis, Genetic; Cognition
PubMed: 37759260
DOI: 10.1186/s13024-023-00632-5 -
Brain Research Dec 2023Beta-hydroxybutyrate (BHB), an endogenous NLRP3 inflammasome inhibitor, has been shown to be associated with the pathophysiology of depression in rodents. However its...
Infusions of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produce antidepressant-like effects on learned helplessness rats through BDNF-TrkB signaling and AMPA receptor activation, and strengthen learning ability.
Beta-hydroxybutyrate (BHB), an endogenous NLRP3 inflammasome inhibitor, has been shown to be associated with the pathophysiology of depression in rodents. However its active mechanism has not been revealed. Herein, we probed both the pathways and brain regions involved in BHB's antidepressant-like effects in a learned helplessness (LH) rat model of depression. A single bilateral infusion of BHB into the cerebral ventricles induced the antidepressant-like effects on the LH rats. The antidepressant-like effects of BHB were blocked by the TrkB inhibitor ANA-12 and the AMPA receptor antagonist NBQX, indicating that the antidepressant-like effects of BHB involve BDNF-TrkB signaling and AMPA receptor activation. Further, infusions of BHB into the prelimbic and infralimbic portions of medial prefrontal cortex, the dentate gyrus of hippocampus, and the basolateral region of amygdala produced the antidepressant-like effects on LH rats. However, infusions of BHB into the central region of amygdala, the CA3 region of hippocampus, and the shell and core regions of nucleus accumbens had no effect. Finally, a single bilateral infusion of BHB into the cerebral ventricles of naive rats strengthened learning ability on repeated active avoidance test where saline-infused animals failed to increase avoidance responses.
Topics: Rats; Animals; Helplessness, Learned; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; 3-Hydroxybutyric Acid; Brain-Derived Neurotrophic Factor; Receptors, AMPA; Antidepressive Agents; Depression; Receptor, trkB
PubMed: 37689333
DOI: 10.1016/j.brainres.2023.148567