Propionic Acid Receptor Research Articles

GluA2-lacking AMPA receptors in the nucleus accumbens core and shell contribute to the incubation of oxycodone craving in male rats.

One of the most challenging issues in the treatment of substance use disorder, including misuse of opioids such as oxycodone, is persistent vulnerability to relapse, often triggered by cues or contexts previously associated with drug use. In rats, cue-induced craving progressively intensifies ('incubates') during withdrawal from extended-access self-administration of several classes of misused drugs, including the psychostimulants cocaine and methamphetamine. For these psychostimulants, incubation is associated with strengthening of excitatory synapses in the nucleus accumbens (NAc) through incorporation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors that lack the GluA2 subunit and are therefore Ca2+ -permeable (CP-AMPARs). Once CP-AMPAR upregulation occurs, their stimulation is required for expression of incubation. It is not known if a similar mechanism contributes to incubation of oxycodone craving. Using male rats, we established that incubation occurs by withdrawal day (WD) 15 and persists through WD30. Then, using cell-surface biotinylation, we found that surface levels of the AMPAR subunit GluA1 but not GluA2 are elevated in NAc core and shell of oxycodone rats on WD15, although this wanes by WD30. Next, using intra-NAc injection of the selective CP-AMPAR antagonist Naspm before a seeking test, we demonstrate that CP-AMPAR blockade in either subregion decreases oxycodone seeking on WD15 or WD30 (after incubation), but not WD1, and has no effect in saline self-administering animals. The Naspm results suggest CP-AMPARs persist in synapses through WD30 even if total cell surface levels wane. These results suggest that a common neurobiological mechanism contributes to expression of incubation of craving for oxycodone and psychostimulants.

Anti-tumor effects of perampanel in malignant glioma cells.

Glioblastoma has a poor prognosis even after multimodal treatment, such as surgery, chemotherapy and radiation therapy. Patients with glioblastoma frequently develop epileptic seizures during the clinical course of the disease and often require antiepileptic drugs. Therefore, agents with both antiepileptic and antitumoral effects may be very useful for glioblastoma treatment. Perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, is an antiepileptic drug that is widely used for intractable epilepsy. The present study aimed to assess the potential antitumoral effects of perampanel using malignant glioma cell lines. The cell proliferation inhibitory effect was evaluated using six malignant glioma cell lines (A-172, AM-38, T98G, U-138MG, U-251MG and YH-13). A dose-dependent inhibitory effect of perampanel on cell viability was demonstrated; however, the sensitivity of cells to perampanel varied and further antitumoral effects were demonstrated in combination with temozolomide (TMZ) in certain malignant glioma cells. Furthermore, cell cycle distribution and apoptosis induction analyses were performed in T98G and U-251MG cells using a fluorescence activated cell sorter (FACS) and the expression levels of apoptosis-related proteins were evaluated using western blotting. No significant change was demonstrated in the proportions of cells in the G0/G1, S and G2/M phases under 1.0 µM perampanel treatment, whereas induction of apoptosis was demonstrated using FACS at 10 µM perampanel and western blotting at 1.0 µM perampanel in both glioma cell lines. Overexpression of SERPINE1 may be related to poor prognosis in patients with gliomas. The combination of 1.0 µM perampanel and 5.0 µM tiplaxtinin, a SERPINE1 inhibitor, demonstrated further reduced cell viability in perampanel-resistant U-138MG cells, which have high expression levels of SERPINE1. These results indicated that the antitumor effect of perampanel may not be expected for malignant gliomas with higher expression levels of SERPINE1. The findings of the present study suggested that the antiepileptic drug perampanel may also have an antitumor effect through the induction of apoptosis, which is increased when combined with TMZ in certain malignant glioma cells. These findings also suggested that SERPINE1 expression may be involved in perampanel susceptibility. These results may lead to new therapeutic strategies for malignant glioma.

L-4-Fluorophenylglycine produces antidepressant-like effects and enhances resilience to stress in mice

D-serine has attracted increasing attention for its possible role in depression. L-4-Fluorophenylglycine (L-4FPG), an inhibitor of the neutral amino acid transporter ASCT1/2, has been shown to regulate extracellular D-serine levels. The present study aimed to explore the potential antidepressant effects of L-4FPG. First, the acute effects of L-4FPG on the forced swimming test, elevated plus maze test, and novelty-suppressed feeding test were examined. L-4FPG showed antidepressant-like effects, which could be reversed by rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist. The phosphorylation levels of mTOR and GluR1 in the hippocampus were also increased after L-4FPG treatment. Next, the therapeutic effects of L-4FPG were examined in a chronic social defeat stress (CSDS) model of depression. L-4FPG ameliorated depression-like behaviors in mice subjected to CSDS. Furthermore, treatment with L-4FPG prior to each social defeat stress session not only decreased defensive behaviors but also prevented CSDS-induced social avoidance and anxiety-like and depression-like behaviors. These findings suggest that L-4FPG may be useful not only in alleviating depression but also in protecting against chronic stress-related psychiatric disorders.

NMDA receptors: Biological properties and their roles in neuropsychiatric disorders

Proper signal transmission is the fundamental process of the brain activity. Changes and adaption of neuroplasticity based on the strength of synaptic transmission are essential for the information propagation in the central nervous system, which contribute to cognition, learning, and memory. Being the major excitatory neurotransmitter in the central nervous system, glutamate acts primarily through binding to the glutamate receptors, the glutamate-gated ion channels localized on post-synaptic membrane. The ionotropic glutamate receptors, pharmacologically grouped into α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, N-methyl-D-aspartic acid (NMDA) receptors, and kainate receptors, have been shown to play distinct roles in excitatory neurotransmission and synaptic plasticity. Due to their high permeability to Ca2+, the NMDA receptors have very unique function in neurotransmission and particular importance in the induction of long-term synaptic plasticity. Dysfunction of NMDA receptors causes impairment in synaptic plasticity and learning and memory. In recent years, with the development of genome-wide association studies and next-generation sequencing technology, mutations of NMDA receptor subunits have been in a variety of neuropsychiatric disorders, such as cognitive impairment, schizophrenia, autism or epilepsy. In clinical practice, NMDA receptors are known as the targets for the treatment of many neuropsychiatric disorders. In current review, we summarize current knowledge of NMDA receptors with different subunit compositions in the context of expression pattern, channel properties, protein trafficking, and synaptic plasticity as well as their roles in neuropsychiatric disorders.

Immunocytochemical localization of the AMPA glutamate receptor subtype GluR2/3 in the squid optic lobe

As a major excitatory neurotransmitter in the cephalopod visual system, glutamate signaling is facilitated by ionotropic receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR). In cephalopods with large and well-developed brains, the optic lobes (OL) mainly process visual inputs and are involved in learning and memory. Although the presence of AMPAR in squid OL has been reported, the organization of specific AMPAR-containing neurons remains unknown. This study aimed to investigate the immunocytochemical localization of the AMPA glutamate receptor subtype 2/3-immunoreactive (GluR2/3-IR) neurons in the OL of Pacific flying squid (Tordarodes pacificus). Morphologically diverse GluR2/3-IR neurons were predominantly located in the tangential zone of the medulla. Medium-to-large GluR2/3-IR neurons were also detected. The distribution patterns and cell morphologies of calcium-binding protein (CBP)-IR neurons, specifically calbindin-D28K (CB)-, calretinin (CR)-, and parvalbumin (PV)-IR neurons, were similar to those of GluR2/3-IR neurons. However, two-color immunofluorescence revealed that GluR2/3-IR neurons did not colocalize with the CBP-IR neurons. Furthermore, the specific localizations and diverse types of GluR2/3-IR neurons that do not express CB, CR, or PV in squid OL were determined. These findings further contribute to the existing data on glutamatergic visual systems and provide new insights for understanding the visual processing mechanisms in cephalopods.

Antinociceptive and Analgesic Effects of (2R,6R)-Hydroxynorketamine.

Commonly used pain therapeutics, such as opioid medications, exert dangerous side effects and lack effectiveness in treating some types of pain. Ketamine is also used to treat pain, but side effects limit its widespread use. (2R,6R)-hydroxynorketamine (HNK) is a ketamine metabolite that potentially shares some beneficial behavioral effects of its parent drug without causing significant side effects. This study compared the profile and potential mechanisms mediating the antinociception activity of ketamine and (2R,6R)-HNK in C57BL/6J mice. Additionally, this study compared the reversal of mechanical allodynia by (2R,6R)-HNK with gabapentin in a model of neuropathic pain. Unlike the near-immediate and short-lived antinociception caused by ketamine, (2R,6R)-HNK produced late-developing antinociception 24 hours following administration. Pharmacological blockade of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) prevented the initiation and expressionof (2R,6R)-HNK antinociception, suggesting the involvement of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-dependent glutamatergic mechanisms in the pain reduction-like responses. Blockade of opioid receptors with naltrexone partially prevented the antinociceptive effect of ketamine but was ineffective against (2R,6R)-HNK. Furthermore, (2R,6R)-HNK did not produce dystaxia, even when tested at doses five times greater than those needed to produce antinociception, indicating a superior safety profile for (2R,6R)-HNK over ketamine. Additionally, (2R,6R)-HNK reversed mechanical allodynia in a spared nerve injury model of neuropathic pain with similar short-term efficacy to gabapentin (within 4 hours) while outperforming gabapentin 24 hours after administration. These findings support the further study of (2R,6R)-HNK as a potentially valuable agent for treating different types of pain and establish certain advantages of (2R,6R)-HNK treatment over ketamine and gabapentin in corresponding assays for pain. SIGNIFICANCE STATEMENT: The ketamine metabolite (2R,6R)-HNK produced antinociception in male and female mice 24 hours after administration via activation of AMPA receptors. The effects of (2R,6R)-HNK differed in time course and mechanism and presented a better safety profile than ketamine. (2R,6R)-HNK also reversed allodynia in SNI-operated animals within 4 hours of treatment onset, with a duration of effect lasting longer than gabapentin. Taken together, (2R,6R)-HNK demonstrates the potential for development as a non-opioid analgesic drug.

Altered Calcium Permeability of AMPA Receptor Drives NMDA Receptor Inhibition in the Hippocampus of Murine Obesity Models.

Evidence has accumulated that higher consumption of high-fat diets (HFDs) during the juvenile/adolescent period induces altered hippocampal function and morphology; however, the mechanism behind this phenomenon remains elusive. Using high-resolution structural imaging combined with molecular and functional interrogation, a murine model of obesity treated with HFDs for 12weeks after weaning mice was shown to change in the glutamate-mediated intracellular calcium signaling and activity, including further selective reduction of gray matter volume in the hippocampus associated with memory recall disturbance. Dysregulation of intracellular calcium concentrations was restored by a non-competitive α-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) antagonist, followed by normalization of hippocampal volume and memory recall ability, indicating that AMPARs may serve as an attractive therapeutic target for obesity-associated cognitive decline.

Synapse differentiation-induced gene 1 regulates stress-induced depression through interaction with the AMPA receptor GluA2 subunit of nucleus accumbens in male mice

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are key regulators during the process of synaptic plasticity in major depression disorder (MDD). Synapse differentiation-induced gene 1 (SynDIG1) functions as an atypical AMPAR auxiliary subunit and regulates synaptic AMPAR content; however, the role of SynDIG1 in MDD remains elusive. In this study, we found that the SynDIG1 expression was significantly increased in the neurons of the nucleus accumbens (NAc) of male mice after chronic social defeat stress (CSDS). CSDS enhanced SynDIG1-GluA2 binding and promoted the surface expression of AMPAR subunit GluA2 in the NAc. Knockdown of SynDIG1 decreased the surface expression of GluA2 and reversed the alteration of dendrite spines in the neurons, eventually alleviating the depressive-like behaviors of the stressed mice. Moreover, intra-NAc injection of IP12, a specific peptide to disrupt the interaction of SynDIG1 with GluA2, rescued depressive-like behaviors. Collectively, SynDIG1 regulates the surface expression of GluA2 and dendritic remodeling in the NAc of male mice under CSDS, thus mediating the depressive-like behaviors.

Repeated vagus nerve stimulation produces anxiolytic effects via upregulation of AMPAR function in centrolateral amygdala of male rats

Repeated vagus nerve stimulation (rVNS) exerts anxiolytic effect by activation of noradrenergic pathway. Centrolateral amygdala (CeL), a lateral subdivision of central amygdala, receives noradrenergic inputs, and its neuronal activity is positively correlated to anxiolytic effect of benzodiazepines. The activation of β-adrenergic receptors (β-ARs) could enhance glutamatergic transmission in CeL. However, it is unclear whether the neurobiological mechanism of noradrenergic system in CeL mediates the anxiolytic effect induced by rVNS. Here, we find that rVNS treatment produces an anxiolytic effect in male rats by increasing the neuronal activity of CeL. Electrophysiology recording reveals that rVNS treatment enhances the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-mediated excitatory neurotransmission in CeL, which is mimicked by β-ARs agonist isoproterenol or blocked by β-ARs antagonist propranolol. Moreover, chemogenetic inhibition of CeL neurons or pharmacological inhibition of β-ARs in CeL intercepts both enhanced glutamatergic neurotransmission and the anxiolytic effects by rVNS treatment. These results suggest that the amplified AMPAR trafficking in CeL via activation of β-ARs is critical for the anxiolytic effects induced by rVNS treatment.

Rare coding variants in ten genes confer substantial risk for schizophrenia.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of theNMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

NMDA and AMPA receptor physiology and role in visceral hypersensitivity: a review.

N-methyl-d-aspartate receptors (NMDARs) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are excitatory neurotransmission receptors of the central nervous system and play vital roles in synaptic plasticity. Although not fully elucidated, visceral hypersensitivity is one of the most well-characterized pathophysiologic abnormalities of functional gastrointestinal diseases and appears to be associated with increased synaptic plasticity. In this study, we review the updated findings on the physiology of NMDARs and AMPARs and their relation to visceral hypersensitivity, which propose directions for future research in this field with evolving importance.

The effect of novel negative allosteric 2,3-benzodiazepine on glutamate AMPA receptor and their cytotoxicity

2,3-Benzodiazepine (2,3-BDZ) compounds represent a group of structurally varied antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor. AMPA receptor antagonists are required to treat AMPA receptor anomalies associated with neurological illnesses, including epilepsy and stroke. Five new 2,3-BDZ compounds were tested on AMPA receptors using patch-clamp electrophysiology, while cancer cells (i.e., Hep3B, HepG2, Hela, and MCF-7) were examined using the MTS assay. Our findings indicated that adding an electron-withdrawing group (i.e., Cl or Br) inhibited AMPA receptors the most in reducing AMPA receptor cell currents and affecting the kinetics of AMPA receptors (i.e., desensitization and deactivation). Moreover, the phenyl ring of 2,3-benzodiazepine is critical for AMPA receptor binding to the affected compounds. In addition, 4b and 4e showed a potential cytotoxicity effect against Hep3B, HepG2, Hela, and MCF-7, especially Hep3B. 2,3-benzodiazepine derivatives showed neuroprotection against AMPA receptors and cytotoxicity that may be employed in several applications.

The Shaping of AMPA Receptor Surface Distribution by Neuronal Activity.

Neurotransmission is critically dependent on the number, position, and composition of receptor proteins on the postsynaptic neuron. Of these, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are responsible for the majority of postsynaptic depolarization at excitatory mammalian synapses following glutamate release. AMPARs are continually trafficked to and from the cell surface, and once at the surface, AMPARs laterally diffuse in and out of synaptic domains. Moreover, the subcellular distribution of AMPARs is shaped by patterns of activity, as classically demonstrated by the synaptic insertion or removal of AMPARs following the induction of long-term potentiation (LTP) and long-term depression (LTD), respectively. Crucially, there are many subtleties in the regulation of AMPARs, and exactly how local and global synaptic activity drives the trafficking and retention of synaptic AMPARs of different subtypes continues to attract attention. Here we will review how activity can have differential effects on AMPAR distribution and trafficking along with its subunit composition and phosphorylation state, and we highlight some of the controversies and remaining questions. As the AMPAR field is extensive, to say the least, this review will focus primarily on cellular and molecular studies in the hippocampus. We apologise to authors whose work could not be cited directly owing to space limitations.

BDNF-TrkB signaling-mediated upregulation of Narp is involved in the antidepressant-like effects of (2R,6R)-hydroxynorketamine in a chronic restraint stress mouse model

BackgroundPreclinical studies have indicated that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) is a rapid-acting antidepressant drug with limited dissociation properties and low abuse potential. However, its effects and molecular mechanisms remain unclear. In this work, we examined the involvement of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and Narp in the antidepressant-like actions of (2R,6R)-HNK in a chronic restraint stress (CRS) mouse model.MethodsC57BL/6 male mice were subjected to CRS for 8 h per day for 14 consecutive days. Open field, forced swimming, novelty suppressed feeding, and tail suspension tests were performed after administering (2R,6R)-HNK (10 mg/kg), a combination of (2R,6R)-HNK and NBQX (an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist; 10 mg/kg), or a combination of (2R,6R)-HNK and ANA-12 (a TrkB receptor antagonist; 0.5 mg/kg). The mRNA levels of Bdnf and Narp in the hippocampus were determined by quantitative reverse transcription-PCR (qRT–PCR). Western blotting was used to determine the hippocampal protein levels of GluA1, GluA2, BDNF, Narp, PSD95, and synaptophysin, as well as the p-TrkB/TrkB protein ratio.Results(2R,6R)-HNK had rapid antidepressant-like effects in CRS mice. Furthermore, (2R,6R)-HNK significantly ameliorated CRS-induced downregulation of GluA1, GluA2, BDNF, Narp, PSD95, and the p-TrkB/TrkB protein ratio in the hippocampus. The effects of (2R,6R)-HNK were blocked by combinations with NBQX or ANA-12.ConclusionBDNF-TrkB signaling-mediated upregulation of Narp in the hippocampus may play a key role in the antidepressant-like effect of (2R,6R)-HNK in the CRS model of depression.

Epileptic discharges initiate from brain areas with elevated accumulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors.

Presurgical identification of the epileptogenic zone is a critical determinant of seizure control following surgical resection in epilepsy. Excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor is a major component of neurotransmission. Although elevated α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor levels are observed in surgically resected brain areas of patients with epilepsy, it remains unclear whether increased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated currents initiate epileptic discharges. We have recently developed the first PET tracer for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, [11C]K-2, to visualize and quantify the density of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in living human brains. Here, we detected elevated [11C]K-2 uptake in the epileptogenic temporal lobe of patients with mesial temporal lobe epilepsy. Brain areas with high [11C]K-2 uptake are closely colocalized with the location of equivalent current dipoles estimated by magnetoencephalography or with seizure onset zones detected by intracranial electroencephalogram. These results suggest that epileptic discharges initiate from brain areas with increased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, providing a biological basis for epileptic discharges and an additional non-invasive option to identify the epileptogenic zone in patients with mesial temporal lobe epilepsy.

The Effects of Intraoperative Hypothermia on Postoperative Cognitive Function in the Rat Hippocampus and Its Possible Mechanisms.

Intraoperative hypothermia is a common complication during operations and is associated with several adverse events. Postoperative cognitive dysfunction (POCD) and its adverse consequences have drawn increasing attention in recent years. There are currently no relevant studies investigating the correlation between intraoperative hypothermia and POCD. The aim of this study was to assess the effects of intraoperative hypothermia on postoperative cognitive function in rats undergoing exploratory laparotomies and to investigate the possible related mechanisms. We used the Y-maze and Morris Water Maze (MWM) tests to assess the rats’ postoperative spatial working memory, spatial learning, and memory. The morphological changes in hippocampal neurons were examined by haematoxylin-eosin (HE) staining and hippocampal synaptic plasticity-related protein expression. Activity-regulated cytoskeletal-associated protein (Arc), cyclic adenosine monophosphate-response element-binding protein (CREB), S133-phosphorylated CREB (p-CREB [S133]), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor 1 (AMPAR1), and S831-phosphorylated AMPAR1 (p-AMPAR1 [S831]) were evaluated by Western blotting. Our results suggest a correlation between intraoperative hypothermia and POCD in rats and that intraoperative hypothermia may lead to POCD regarding impairments in spatial working memory, spatial learning, and memory. POCD induced by intraoperative hypothermia might be due to hippocampal neurons damage and decreased expression of synaptic plasticity-related proteins Arc, p-CREB (S133), and p-AMPAR1 (S831).

Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model.

In motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, the RNA editing at the glutamine/arginine site of the GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors is defective or incomplete. As a result, AMPA receptors containing the abnormally expressed, unedited isoform of GluA2 are highly Ca2+-permeable, and are responsible for mediating abnormal Ca2+ influx, thereby triggering motor neuron degeneration and cell death. Thus, blocking the AMPA receptor-mediated, abnormal Ca2+ influx is a potential therapeutic strategy for treatment of sporadic ALS. Here, we report a study of the efficacy and safety of two RNA aptamers targeting AMPA receptors on the ALS phenotype of AR2 mice. A 12-wk continuous, intracerebroventricular infusion of aptamers to AR2 mice reduced the progression of motor dysfunction, normalized TDP-43 mislocalization, and prevented death of motor neurons. Our results demonstrate that the use of AMPA receptor aptamers as a novel class of AMPA receptor antagonists is a promising strategy for developing an ALS treatment approach.

Effects of perampanel on cognitive behavior and GluR1 expression in immature mice of temporal lobe epilepsy

Temporal lobe epilepsy (TLE) has a low antiepileptic drug (AED) treatment response rate, and about 70% of patients eventually progress to refractory epilepsy. Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, which is used clinically for the treatment of partially refractory epilepsy, but its mechanism of action is not completely clear. In this study, kainic acid (KA) was successfully used to induce TLE in 3-week-old C57BL/6 immature mice, and the effects of PER on the cognitive behavior of the epileptic mice were characterized using the Morris water maze paradigm. To determine the mechanism underlying the therapeutic effects of PER, the morphological evolution of the hippocampus and the expression of AP-1 and GluR1 were systematically evaluated. Compared to control TLE mice, escape latency was reduced and the number of target platform crossings was increased in the Morris water maze by treatment with PER. The therapeutic effects of PER were mediated mainly via inhibition of the expression of AP-1 and GluR1, as the TLE mice showed significantly improved learning and memory and decreased seizure frequency after treatment with PER.

Anterior Cingulate Cortex Mediates Hyperalgesia and Anxiety Induced by Chronic Pancreatitis in Rats

Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. Here, we examined the role of the anterior cingulate cortex (ACC) in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats. Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii (NTS) and ACC, and some FOS-expressing neurons in the NTS projected to the ACC. In addition, a larger portion of ascending fibers from the NTS innervated pyramidal neurons, the neural subpopulation primarily expressing FOS under the condition of painful CP, rather than GABAergic neurons within the ACC. CP rats showed increased expression of vesicular glutamate transporter 1, and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) subunit NR2B and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluR1 within the ACC. Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats, which was similar to the analgesic effect of endomorphins injected into the ACC. Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety, whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats. Taken together, these findings provide neurocircuit, biochemical, and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats, as well as novel insights into the cortical modulation of painful CP, and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.

Cornel iridoid glycoside protects against STAT1‐dependent synapse and memory deficits by increasing NMDA receptor expression in tau transgenic mice

AbstractBackgroundP301S transgenic mice is an animal model of tauopathy and Alzheimer’s disease (AD), exhibiting tau pathology and synaptic dysfunction. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S mice.MethodIntragastric administration of CIG for 3.5 months was applied to P301S mice from 9‐month‐old to 12.5‐month‐old of age. Objective recognition test and Y maze task were used to test the cognitive impairments of P301S mice. Electrophysiological recording was applied to record long‐term potential. Transmission electron microscopy was used to investigate the the ultrastructure and number of synapse. Immunohistochemical staining was applied to detect tau phosphorylation. Western blotting was used to detect the expression levels of related proteins.ResultsIntragastric administration of CIG for 3.5 months improved learning and memory abilities, increased the survival rate of P301S mice. Electrophysiological recordings and transmission Electron microscopy study showed that CIG improved synaptic plasticity, increased the ultrastructure and number of synapse. Moreover, CIG increased the expression of N‐methyl‐D‐aspartate receptors (NMDARs) subunits GluN1, GluN2A and GluN2B, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor (AMPAR) subunit GluA1. The major mechanism of CIG involved in the regulation of synaptic dysfunction was to inhibited the activation of Janus kinase‐2 (JAK2) /signal transducer and activator of transcription 1 (STAT1) signaling pathway and STAT1‐induced suppression of NMDAR expression.ConclusionBased on our findings, CIG might be a promising candidate for the prevention of tauopathy such as AD.