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Communications Biology Mar 2024The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal...
The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key role in brain's processing of rewarding/aversive experiences, however its role in the lateral habenula (LHb, as an important brain reward circuitry) is completely unknown. Using whole cell patch clamp recordings in LHb of male wildtype and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), here we show that the genetic disruption of PKA anchoring to AKAP150 significantly reduces AMPA receptor-mediated glutamatergic transmission and prevents the induction of presynaptic endocannabinoid-mediated long-term depression in LHb neurons. Moreover, ΔPKA mutation potentiates GABA receptor-mediated inhibitory transmission while increasing LHb intrinsic excitability through suppression of medium afterhyperpolarizations. ΔPKA mutation-induced suppression of medium afterhyperpolarizations also blunts the synaptic and neuroexcitatory actions of the stress neuromodulator, corticotropin releasing factor (CRF), in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPA and GABA receptor synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPA receptor and potassium channel trafficking and endocannabinoid signaling within the LHb.
Topics: Animals; Male; Mice; A Kinase Anchor Proteins; Corticotropin-Releasing Hormone; Endocannabinoids; Habenula; Neuronal Plasticity; Neurons; Receptors, AMPA; Receptors, GABA-A; Synaptic Transmission
PubMed: 38509283
DOI: 10.1038/s42003-024-06041-8 -
Cell Reports Apr 2024Perceptual learning improves our ability to interpret sensory stimuli present in our environment through experience. Despite its importance, the underlying mechanisms...
Perceptual learning improves our ability to interpret sensory stimuli present in our environment through experience. Despite its importance, the underlying mechanisms that enable perceptual learning in our sensory cortices are still not fully understood. In this study, we used in vivo two-photon imaging to investigate the functional and structural changes induced by visual stimulation in the mouse primary visual cortex (V1). Our results demonstrate that repeated stimulation leads to a refinement of V1 circuitry by decreasing the number of responsive neurons while potentiating their response. At the synaptic level, we observe a reduction in the number of dendritic spines and an overall increase in spine AMPA receptor levels in the same subset of neurons. In addition, visual stimulation induces synaptic potentiation in neighboring spines within individual dendrites. These findings provide insights into the mechanisms of synaptic plasticity underlying information processing in the neocortex.
Topics: Animals; Neuronal Plasticity; Mice; Primary Visual Cortex; Dendritic Spines; Receptors, AMPA; Photic Stimulation; Mice, Inbred C57BL; Synapses; Neurons; Visual Cortex
PubMed: 38507408
DOI: 10.1016/j.celrep.2024.113966 -
American Journal of Nuclear Medicine... 2024Several therapeutics and biomarkers that target Alzheimer's disease (AD) are under development. Our clinical positron emission tomography (PET) research programs are...
Several therapeutics and biomarkers that target Alzheimer's disease (AD) are under development. Our clinical positron emission tomography (PET) research programs are interested in six radiopharmaceuticals to image patients with AD and related dementias, specifically [C]UCB-J and [F]SynVesT-1 for synaptic vesicle glycoprotein 2A as a marker of synaptic density, two vesicular acetylcholine transporter PET radiotracers: [F]FEOBV and [F]VAT, as well as the transmembrane AMPA receptor regulatory protein (TARP)-γ8 tracer, [F]JNJ-64511070, and the muscarinic acetylcholine receptor (mAChR) M4 tracer [C]MK-6884. The goal of this study was to compare all six radiotracers (labeled with tritium or F) by measuring their density variability in pathologically diagnosed cases of AD, mild cognitive impairment (MCI) and normal healthy volunteer (NHV) human brains, using thin-section autoradiography (ARG). Region of interest analysis was used to quantify radioligand binding density and determine whether the radioligands provide a signal-to-noise ratio optimal for showing changes in binding. Our preliminary study confirmed that all six radiotracers show specific binding in MCI and AD. An expected decrease in their respective target density in human AD hippocampus tissues compared to NHV was observed with [H]UCB-J, [H]SynVesT-1, [H]JNJ-64511070, and [H]MK-6884. This preliminary study will be used to guide human PET imaging of SV2A, TARP-γ8 and the mAChR M4 subtype for imaging in AD and related dementias.
PubMed: 38500748
DOI: 10.62347/USWK7545 -
American Journal of Nuclear Medicine... 2024In the current issue of American Journal of Nuclear Medicine and Molecular Imaging, Vasdev et al. presented a work entitled "In Vitro Evaluation of PET Radiotracers for...
In the current issue of American Journal of Nuclear Medicine and Molecular Imaging, Vasdev et al. presented a work entitled "In Vitro Evaluation of PET Radiotracers for Imaging Synaptic Density, the Acetylcholine Transporter, AMPA-tarp-γ8 and Muscarinic M4 receptors in Alzheimer's disease". In which, in vitro autoradiography studies using radioligands were employed as a valuable tool to gain more insights for potential clinical translation. In this invited perspective, we would like to briefly introduce the current state of AD diagnosis, especially PET imaging on synapse, and highlight the advances of PET imaging in pre-clinic and clinic that might assist on precise therapy in the future.
PubMed: 38500741
DOI: 10.62347/KSJB6678 -
CNS Neuroscience & Therapeutics Mar 2024General anesthesia has been used in surgical procedures for approximately 180 years, yet the precise mechanism of anesthetic drugs remains elusive. There is...
AIMS
General anesthesia has been used in surgical procedures for approximately 180 years, yet the precise mechanism of anesthetic drugs remains elusive. There is significant anatomical connectivity between the ventral tegmental area (VTA) and the prelimbic cortex (PrL). Projections from VTA dopaminergic neurons (VTA ) to the PrL play a role in the transition from sevoflurane anesthesia to arousal. It is still uncertain whether the prelimbic cortex pyramidal neuron (PrL ) and its projections to VTA (PrL -VTA) are involved in anesthesia-arousal regulation.
METHODS
We employed chemogenetics and optogenetics to selectively manipulate neuronal activity in the PrL -VTA pathway. Electroencephalography spectra and burst-suppression ratios (BSR) were used to assess the depth of anesthesia. Furthermore, the loss or recovery of the righting reflex was monitored to indicate the induction or emergence time of general anesthesia. To elucidate the receptor mechanisms in the PrL -VTA projection's impact on anesthesia and arousal, we microinjected NMDA receptor antagonists (MK-801) or AMPA receptor antagonists (NBQX) into the VTA.
RESULTS
Our findings show that chemogenetic or optogenetic activation of PrL neurons prolonged anesthesia induction and promoted emergence. Additionally, chemogenetic activation of the PrL -VTA neural pathway delayed anesthesia induction and promoted anesthesia emergence. Likewise, optogenetic activation of the PrL -VTA projections extended the induction time and facilitated emergence from sevoflurane anesthesia. Moreover, antagonizing NMDA receptors in the VTA attenuates the delayed anesthesia induction and promotes emergence caused by activating the PrL -VTA projections.
CONCLUSION
This study demonstrates that PrL neurons and their projections to the VTA are involved in facilitating emergence from sevoflurane anesthesia, with the PrL -VTA pathway exerting its effects through the activation of NMDA receptors within the VTA.
Topics: Ventral Tegmental Area; Sevoflurane; Receptors, N-Methyl-D-Aspartate; Dopaminergic Neurons; Pyramidal Cells; Anesthesia, General; Arousal
PubMed: 38488453
DOI: 10.1111/cns.14675 -
Brain, Behavior, and Immunity May 2024Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%-25% of patients with frontotemporal lobar degeneration...
Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%-25% of patients with frontotemporal lobar degeneration (FTLD). Data from patients and in vitro/ex vivo pre-clinical studies indicate that anti-GluA3 hIgGs negatively affect glutamatergic neurotransmission. However, whether and how the chronic presence of anti-GluA3 hIgGs triggers synaptic dysfunctions and the appearance of FTLD-related neuropathological and behavioural signature has not been clarified yet. To address this question, we developed and characterized a pre-clinical mouse model of passive immunization with anti-GluA3 hIgGs purified from patients. In parallel, we clinically compared FTLD patients who were positive for anti-GluA3 hIgGs to negative ones. Clinical data showed that the presence of anti-GluA3 hIgGs defined a subgroup of patients with distinct clinical features. In the preclinical model, anti-GluA3 hIgGs administration led to accumulation of phospho-tau in the postsynaptic fraction and dendritic spine loss in the prefrontal cortex. Remarkably, the preclinical model exhibited behavioural disturbances that mostly reflected the deficits proper of patients positive for anti-GluA3 hIgGs. Of note, anti-GluA3 hIgGs-mediated alterations were rescued in the animal model by enhancing glutamatergic neurotransmission with a positive allosteric modulator of AMPA receptors. Overall, our study clarified the contribution of anti-GluA3 autoantibodies to central nervous system symptoms and pathology and identified a specific subgroup of FTLD patients. Our findings will be instrumental in the development of a therapeutic personalised medicine strategy for patients positive for anti-GluA3 hIgGs.
Topics: Animals; Humans; Mice; Autoantibodies; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Receptors, AMPA; Synaptic Transmission; tau Proteins
PubMed: 38485064
DOI: 10.1016/j.bbi.2024.03.018 -
ELife Mar 2024Our understanding of mitochondrial signaling in the nervous system has been limited by the technical challenge of analyzing mitochondrial function in vivo. In the...
Our understanding of mitochondrial signaling in the nervous system has been limited by the technical challenge of analyzing mitochondrial function in vivo. In the transparent genetic model we were able to manipulate and measure mitochondrial reactive oxygen species (mitoROS) signaling of individual mitochondria as well as neuronal activity of single neurons in vivo. Using this approach, we provide evidence supporting a novel role for mitoROS signaling in dendrites of excitatory glutamatergic interneurons. Specifically, we show that following neuronal activity, dendritic mitochondria take up calcium (Ca) via the mitochondrial Ca uniporter (MCU-1) that results in an upregulation of mitoROS production. We also observed that mitochondria are positioned in close proximity to synaptic clusters of GLR-1, the ortholog of the AMPA subtype of glutamate receptors that mediate neuronal excitation. We show that synaptic recruitment of GLR-1 is upregulated when MCU-1 function is pharmacologically or genetically impaired but is downregulated by mitoROS signaling. Thus, signaling from postsynaptic mitochondria may regulate excitatory synapse function to maintain neuronal homeostasis by preventing excitotoxicity and energy depletion.
Topics: Animals; Caenorhabditis elegans; Reactive Oxygen Species; Receptors, Glutamate; Neurons; Synapses; Calcium
PubMed: 38483244
DOI: 10.7554/eLife.92376 -
Communications Biology Mar 2024Ubiquitin modifications alter protein function and stability, thereby regulating cell homeostasis and viability, particularly under stress. Ischemic stroke induces...
Ubiquitin modifications alter protein function and stability, thereby regulating cell homeostasis and viability, particularly under stress. Ischemic stroke induces protein ubiquitination at the ischemic periphery, wherein cells remain viable, however the identity of ubiquitinated proteins is unknown. Here, we employed a proteomics approach to identify these proteins in mice undergoing ischemic stroke. The data are available in a searchable web interface ( https://hochrainerlab.shinyapps.io/StrokeUbiOmics/ ). We detected increased ubiquitination of 198 proteins, many of which localize to the postsynaptic density (PSD) of glutamatergic neurons. Among these were proteins essential for maintaining PSD architecture, such as PSD95, as well as NMDA and AMPA receptor subunits. The largest enzymatic group at the PSD with elevated post-ischemic ubiquitination were kinases, such as CaMKII, PKC, Cdk5, and Pyk2, whose aberrant activities are well-known to contribute to post-ischemic neuronal death. Concurrent phospho-proteomics revealed altered PSD-associated phosphorylation patterns, indicative of modified kinase activities following stroke. PSD-located CaMKII, PKC, and Cdk5 activities were decreased while Pyk2 activity was increased after stroke. Removal of ubiquitin restored kinase activities to pre-stroke levels, identifying ubiquitination as the responsible molecular mechanism for post-ischemic kinase regulation. These findings unveil a previously unrecognized role of ubiquitination in the regulation of essential kinases involved in ischemic injury.
Topics: Mice; Animals; Disks Large Homolog 4 Protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Focal Adhesion Kinase 2; Post-Synaptic Density; Phosphotransferases; Ubiquitination; Ischemia; Ubiquitin; Stroke; Ischemic Stroke
PubMed: 38480905
DOI: 10.1038/s42003-024-06009-8 -
Neurobiology of Disease May 2024Emerging evidence has implicated an important role of synapse-associated protein-97 (SAP97)-regulated GluA1-containing AMPARs membrane trafficking in cocaine restate and...
Spinal nerve transection-induced upregulation of SAP97 via promoting membrane trafficking of GluA1-containing AMPA receptors in the dorsal horn contributes to the pathogenesis of neuropathic pain.
Emerging evidence has implicated an important role of synapse-associated protein-97 (SAP97)-regulated GluA1-containing AMPARs membrane trafficking in cocaine restate and in contextual episodic memory of schizophrenia. Herein, we investigated the role of SAP97 in neuropathic pain following lumbar 5 spinal nerve transection (SNT) in rats. Our results showed that SNT led to upregulation of SAP97, enhanced the interaction between SAP97 and GluA1, and increased GluA1-containing AMPARs membrane trafficking in the dorsal horn. Microinjection of AAV-EGFP-SAP97 shRNA in lumbar 5 spinal dorsal horn inhibited SAP97 production, decreased SAP97-GluA1 interaction, reduced the membrane trafficking of GluA1-containing AMPARs, and partially attenuated neuropathic pain following SNT. Intrathecal injections of SAP97 siRNA or NASPM, an antagonist of GluA1-containing AMPARs, also partially reversed neuropathic pain on day 7, but not on day 14, after SNT. Spinal overexpression of SAP97 by AAV-EGFP-SAP97 enhanced SAP97-GluA1 interaction, increased the membrane insertion of GluA1-containing AMPARs, and induced abnormal pain in naïve rats. In addition, treatment with SAP97 siRNA or NASPM i.t. injection alleviated SNT-induced allodynia and hyperalgesia and exhibited a longer effect in female rats. Together, our results indicate that the SNT-induced upregulation of SAP97 via promoting GluA1-containing AMPARs membrane trafficking in the dorsal horn contributes to the pathogenesis of neuropathic pain. Targeting spinal SAP97 might be a promising therapeutic strategy to treatment of chronic pain.
Topics: Animals; Female; Rats; Hyperalgesia; Neuralgia; Rats, Sprague-Dawley; Receptors, AMPA; RNA, Small Interfering; Spermine; Spinal Cord Dorsal Horn; Spinal Nerves; Up-Regulation
PubMed: 38461868
DOI: 10.1016/j.nbd.2024.106471 -
ELife Mar 2024Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA...
Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague-Dawley rats received a unilateral contusion of the T9 spinal cord (n = 10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed 5 d post-SCI under urethane anesthesia. Data were compared to responses in spinal-intact rats (n = 8). The 'low-impact' ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (2-hydroxypropyl-beta-cyclodextrin [HPCD]) was administered intravenously. The HPCD vehicle had no discernible impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume, and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder-voiding capability at subacute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.
Topics: Rats; Female; Animals; Quality of Life; Rats, Sprague-Dawley; Receptors, AMPA; Spinal Cord Injuries; Contusions
PubMed: 38451184
DOI: 10.7554/eLife.89767