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Frontiers in Pharmacology 2023Alzheimer's disease (AD), one of the most prevalent neurodegenerative diseases is associated with pathological autophagy-lysosomal pathway dysfunction. Dexmedetomidine...
Alzheimer's disease (AD), one of the most prevalent neurodegenerative diseases is associated with pathological autophagy-lysosomal pathway dysfunction. Dexmedetomidine (Dex) has been suggested as an adjuvant to general anesthesia with advantages in reducing the incidence of postoperative cognitive dysfunction in Dex-treated patients with AD and older individuals. Several studies reported that Dex improved memory; however, evidence on the effects of Dex on neuronal autophagy dysfunction in the AD model is lacking. We hypothesized that Dex administration would have neuroprotective effects by improving pathological autophagy dysfunction in mice that received an intracerebroventricular (i.c.v.) injection of amyloid β-protein fragment 25-35 (Aβ) and in an autophagy-deficient cellular model. In the Y-maze test, Dex reversed the decreased activity of Aβ mice. Additionally, it restored the levels of two memory-related proteins, phosphorylated Ca/calmodulin-dependent protein kinase II (p-CaMKII) and postsynaptic density-95 (PSD-95) in Aβ mice and organotypic hippocampal slice culture (OHSC) with Aβ. Dex administration also resulted in decreased expression of the autophagy-related microtubule-associated proteins light chain 3-II (LC3-II), p62, lysosome-associated membrane protein2 (LAMP2), and cathepsin D in Aβ mice and OHSC with Aβ. Increased numbers of co-localized puncta of LC3-LAMP2 or LC3-cathepsin D, along with dissociated LC3-p62 immunoreactivity following Dex treatment, were observed. These findings were consistent with the results of western blots and the transformation of double-membrane autophagosomes into single-membraned autolysosomes in ultrastructures. It was evident that Dex treatment alleviated impaired autolysosome formation in Aβ mice. Our study demonstrated the improvement of memory impairment caused by Dex and its neuroprotective mechanism by investigating the role of the autophagy-lysosomal pathway in a murine Aβ model. These findings suggest that Dex could be used as a potential neuroprotective adjuvant in general anesthesia to prevent cognitive decline.
PubMed: 37663257
DOI: 10.3389/fphar.2023.1184776 -
Philosophical Transactions of the Royal... Jul 2024Which proportion of the long-term potentiation (LTP) expressed in the bulk of excitatory synapses is postsynaptic and which presynaptic remains debatable. To understand...
Which proportion of the long-term potentiation (LTP) expressed in the bulk of excitatory synapses is postsynaptic and which presynaptic remains debatable. To understand better the possible impact of either LTP form, we explored a realistic model of a CA1 pyramidal cell equipped with known membrane mechanisms and multiple, stochastic excitatory axo-spinous synapses. Our simulations were designed to establish an input-output transfer function, the dependence between the frequency of presynaptic action potentials triggering probabilistic synaptic discharges and the average frequency of postsynaptic spiking. We found that, within the typical physiological range, potentiation of the postsynaptic current results in a greater overall output than an equivalent increase in presynaptic release probability. This difference grows stronger at lower input frequencies and lower release probabilities. Simulations with a non-hierarchical circular network of principal neurons indicated that equal increases in either synaptic fidelity or synaptic strength of individual connections also produce distinct changes in network activity, although the network phenomenology is likely to be complex. These observations should help to interpret the machinery of LTP phenomena documented . This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Long-Term Potentiation; Models, Neurological; Synapses; Pyramidal Cells; Animals; Computer Simulation; Action Potentials; CA1 Region, Hippocampal
PubMed: 38853561
DOI: 10.1098/rstb.2023.0235 -
The Journal of Neuroscience : the... Jul 2023During the first two postnatal weeks, intraneuronal chloride concentrations in rodents gradually decrease, causing a shift from depolarizing to hyperpolarizing GABA...
During the first two postnatal weeks, intraneuronal chloride concentrations in rodents gradually decrease, causing a shift from depolarizing to hyperpolarizing GABA responses. The postnatal GABA shift is delayed in rodent models for neurodevelopmental disorders and in human patients, but the impact of a delayed GABA shift on the developing brain remains obscure. Here we examine the direct and indirect consequences of a delayed postnatal GABA shift on network development in organotypic hippocampal cultures made from 6- to 7-d-old mice by treating the cultures for 1 week with VU0463271, a specific inhibitor of the chloride exporter KCC2. We verified that VU treatment delayed the GABA shift and kept GABA signaling depolarizing until DIV9. We found that the structural and functional development of excitatory and inhibitory synapses at DIV9 was not affected after VU treatment. In line with previous studies, we observed that GABA signaling was already inhibitory in control and VU-treated postnatal slices. Surprisingly, 14 d after the VU treatment had ended (DIV21), we observed an increased frequency of spontaneous inhibitory postsynaptic currents in CA1 pyramidal cells, while excitatory currents were not changed. Synapse numbers and release probability were unaffected. We found that dendrite-targeting interneurons in the stratum radiatum had an elevated resting membrane potential, while pyramidal cells were less excitable compared with control slices. Our results show that depolarizing GABA signaling does not promote synapse formation after P7, and suggest that postnatal intracellular chloride levels indirectly affect membrane properties in a cell-specific manner. During brain development, the action of neurotransmitter GABA shifts from depolarizing to hyperpolarizing. This shift is a thought to play a critical role in synapse formation. A delayed shift is common in rodent models for neurodevelopmental disorders and in human patients, but its consequences for synaptic development remain obscure. Here, we delayed the GABA shift by 1 week in organotypic hippocampal cultures and carefully examined the consequences for circuit development. We find that delaying the shift has no direct effects on synaptic development, but instead leads to indirect, cell type-specific changes in membrane properties. Our data call for careful assessment of alterations in cellular excitability in neurodevelopmental disorders.
Topics: Animals; Mice; Humans; Chlorides; Hippocampus; Interneurons; Synapses; gamma-Aminobutyric Acid; Synaptic Transmission
PubMed: 37438107
DOI: 10.1523/JNEUROSCI.0251-23.2023 -
Frontiers in Molecular Neuroscience 2023Postsynaptic neurotransmitter receptors and their associated scaffolding proteins assemble into discrete, nanometer-scale subsynaptic domains (SSDs) within the...
Postsynaptic neurotransmitter receptors and their associated scaffolding proteins assemble into discrete, nanometer-scale subsynaptic domains (SSDs) within the postsynaptic membrane at both excitatory and inhibitory synapses. Intriguingly, postsynaptic receptor SSDs are mirrored by closely apposed presynaptic active zones. These trans-synaptic molecular assemblies are thought to be important for efficient neurotransmission because they concentrate postsynaptic receptors near sites of presynaptic neurotransmitter release. While previous studies have characterized the role of synaptic activity in sculpting the number, size, and distribution of postsynaptic SSDs at established synapses, it remains unknown whether neurotransmitter signaling is required for their initial assembly during synapse development. Here, we evaluated synaptic nano-architecture under conditions where presynaptic neurotransmitter release was blocked prior to, and throughout synaptogenesis with tetanus neurotoxin (TeNT). In agreement with previous work, neurotransmitter release was not required for the formation of excitatory or inhibitory synapses. The overall size of the postsynaptic specialization at both excitatory and inhibitory synapses was reduced at chronically silenced synapses. However, both AMPARs and GABARs still coalesced into SSDs, along with their respective scaffold proteins. Presynaptic active zone assemblies, defined by RIM1, were smaller and more numerous at silenced synapses, but maintained alignment with postsynaptic AMPAR SSDs. Thus, basic features of synaptic nano-architecture, including assembly of receptors and scaffolds into trans-synaptically aligned structures, are intrinsic properties that can be further regulated by subsequent activity-dependent mechanisms.
PubMed: 37602191
DOI: 10.3389/fnmol.2023.1232795 -
Experimental Gerontology Nov 2023Sarcopenia involves in the loss of muscle mass associated with aging, which is the major cause of progressive muscle weakness and deterioration in older adults. Muscle...
Sarcopenia involves in the loss of muscle mass associated with aging, which is the major cause of progressive muscle weakness and deterioration in older adults. Muscle atrophy is a direct presentation of sarcopenia, and it greatly contributes to the decline in quality of life among older adults. Neuromuscular junction (NMJ) stability is the key link to maintain muscle function. Besides, the degenerative change of NMJ promotes the process of muscle atrophy in the elderly. Based on previous transcriptome sequencing and bioinformatics analyses of aged muscle, this study used the 18-month-old aged mouse model and the 6-month-old young mouse model to deliberate the role and underlying mechanisms of Cullin-3 (Cul3) in age-related muscle atrophy. The results of reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting analysis showed that the expression of CUL3 increased in aged muscle tissue, while the expression level of postsynaptic membrane nicotinic acetylcholine receptors (nAChRs) decreased significantly, which manfested a negative correlation. Meanwhile, immunofluorescence demonstrated that Cul3 was highly expressed in senile muscle NMJ. The results of ubiquitin indicated that the ubiquitin level of aged muscle nAChRs was evidently increased. Co-immunoprecipitation furtherly verified the correlation between Cul3 and nAChRs. Taken together, Cul3 may mediate the ubiquitination degradation of nAChRs protein at the NMJ site in aged mice, leading to NMJ degeneration and accelerated atrophy of fast-twitch muscle fibers in aged muscle. As a prominent element to maintain the stability of NMJ, Cul3 is supposed to be one of candidate intervention targets in sarcopenia.
Topics: Animals; Mice; Cullin Proteins; Muscle, Skeletal; Muscular Atrophy; Neuromuscular Junction; Quality of Life; Receptors, Nicotinic; Sarcopenia; Ubiquitination; Ubiquitins
PubMed: 37913946
DOI: 10.1016/j.exger.2023.112318 -
Neural Regeneration Research Nov 2023Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase, followed by partial...
Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase, followed by partial self-recovery, and ultimately an equilibrium state of neurological dysfunction. Ferroptosis is a crucial pathological process in many neurodegenerative diseases; however, its role in chronic compressive spinal cord injury remains unclear. In this study, we established a chronic compressive spinal cord injury rat model, which displayed its most severe behavioral and electrophysiological dysfunction at 4 weeks and partial recovery at 8 weeks after compression. Bulk RNA sequencing data identified enriched functional pathways, including ferroptosis, presynapse, and postsynaptic membrane activity at both 4 and 8 weeks following chronic compressive spinal cord injury. Transmission electron microscopy and malondialdehyde quantification assay confirmed that ferroptosis activity peaked at 4 weeks and was attenuated at 8 weeks after chronic compression. Ferroptosis activity was negatively correlated with behavioral score. Immunofluorescence, quantitative polymerase chain reaction, and western blotting showed that expression of the anti-ferroptosis molecules, glutathione peroxidase 4 (GPX4) and MAF BZIP transcription factor G (MafG), in neurons was suppressed at 4 weeks and upregulated at 8 weeks following spinal cord compression. There was a positive correlation between the expression of these two molecules, suggesting that they may work together to contribute to functional recovery following chronic compressive spinal cord injury. In conclusion, our study determined the genome-wide expression profile and ferroptosis activity of a consistently compressed spinal cord at different time points. The results showed that anti-ferroptosis genes, specifically GPX4 and MafG, may be involved in spontaneous neurological recovery at 8 weeks of chronic compressive spinal cord injury. These findings contribute to a better understanding of the mechanisms underlying chronic compressive spinal cord injury and may help identify new therapeutic targets for compressive cervical myelopathy.
PubMed: 37282480
DOI: 10.4103/1673-5374.371378 -
CNS Neuroscience & Therapeutics Sep 2023Electroacupuncture (EA) shows advantages in both clinical practice and depression animal models. Dopaminergic-related dysfunction in the prefrontal cortex (PFC) may be a...
Electroacupuncture alleviated depression-like behaviors in ventromedial prefrontal cortex of chronic unpredictable mild stress-induced rats: Increasing synaptic transmission and phosphorylating dopamine transporter.
AIMS
Electroacupuncture (EA) shows advantages in both clinical practice and depression animal models. Dopaminergic-related dysfunction in the prefrontal cortex (PFC) may be a hidden antidepressant mechanism of EA, where dopamine transporter (DAT) plays an essential role. This study aimed to investigate the synaptic transmission and DAT-related changes of EA in depression.
METHODS
Male Sprague-Dawley rats were subjected to 3-week chronic unpredictable mild stress (CUMS). The successfully modeled rats were then randomly and equally assigned to CUMS, selective serotonin reuptake inhibitor (SSRI), and EA or SSRI + EA groups, followed by a 2-week treatment respectively. After monitoring body weight and behavioral tests of all rats, the ventromedial PFC (vmPFC) tissue was collected for electrophysiology and the expression detection of DAT, phosphorylated DAT (p-DAT), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and trace amine-associated receptor 1 (TAAR1).
RESULTS
Depressive-like behaviors induced by CUMS were alleviated by EA, SSRI, and SSRI + EA treatments through behavioral tests. Compared with CUMS group, EA improved synaptic transmission in vmPFC by upregulating spontaneous excitatory postsynaptic currents amplitude. Molecularly, EA reversed the increased total DAT and p-DAT expression as well as the decreased ratio of p-DAT/total DAT along with the activation of TAAR1, cAMP, and PKA in vmPFC.
CONCLUSION
We speculated that the antidepressant effect of EA was associated with enhanced synaptic transmission in vmPFC, and the upregulated phosphorylation of DAT relevant to TAAR1, cAMP, and PKA may be the potential mechanism.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; Depression; Electroacupuncture; Dopamine Plasma Membrane Transport Proteins; Hippocampus; Antidepressive Agents; Synaptic Transmission; Selective Serotonin Reuptake Inhibitors; Prefrontal Cortex; Disease Models, Animal
PubMed: 37002793
DOI: 10.1111/cns.14200 -
CNS Neuroscience & Therapeutics Oct 2023To investigate astrocyte-related phagocytosis of synapses in the ipsilateral hippocampus after traumatic brain injury (TBI).
AIMS
To investigate astrocyte-related phagocytosis of synapses in the ipsilateral hippocampus after traumatic brain injury (TBI).
METHODS
We performed controlled cortical impact to simulate TBI in mice. Seven days postinjury, we performed cognitive tests, synapse quantification, and examination of astrocytic phagocytosis in association with Megf10 expression.
RESULTS
During the subacute stage post-TBI, we found a reduction in excitatory postsynaptic materials in the ipsilateral hippocampus, which was consistent with poor performance in the cognitive test. The transcriptome data suggested that robust phagocytosis was responsible for this process. Coincidently, we identified phagocytic astrocytes containing secondary lysosomes that were wrapped around the synapses in the ipsilateral hippocampus. Moreover, a significant increase in the co-location of GFAP and PSD-95 in the CA1 region suggested astrocytic engulfment of excitatory postsynaptic proteins. After examining the reported phagocytic pathways, we found that both the transcription level and protein expression of Megf10 were elevated. Co-immunofluorescence of GFAP and Megf10 demonstrated that the expression of Megf10 was spatially upregulated in astrocytes, exclusively in the CA1 region, and was related to the astrocytic engulfment of PSD-95.
CONCLUSION
Our study elaborated that the Megf10-related astrocytic engulfment of PSD-95 in the CA1 region of the ipsilateral hippocampus aggravated cognitive dysfunction following severe TBI.
Topics: Mice; Animals; Astrocytes; Hippocampus; Brain Injuries, Traumatic; Disks Large Homolog 4 Protein; Synapses; Membrane Proteins
PubMed: 37081759
DOI: 10.1111/cns.14223 -
Biophysical Reviews Apr 2024This Commentary presents a brief discussion of the action of glutamate calcium permeable receptors present with neurons on the release of the neurotransmitter... (Review)
Review
This Commentary presents a brief discussion of the action of glutamate calcium permeable receptors present with neurons on the release of the neurotransmitter gamma-aminobutyric acid (GABA). In particular, Glutamate sensitive Kainic Acid Receptors (KARs) and α-Amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid Receptor (AMPARs) are Na channels that typically cause neuronal cells to depolarize and release GABA. Some of these receptors are also permeable to Ca and are hence involved in the calcium-dependent release of GABA neurotransmitters. Calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs) are predominantly located in GABAergic neurons in the mature brain and their primary role is to regulate GABA release. AMPARs which do not contain the GluA2 subunit are mainly localized in the postsynaptic membrane. CP-KAR receptors are located mainly in the presynapse. GABAergic neurons expressing CP-KARs and CP-AMPARs respond to excitation earlier and faster, suppressing hyperexcitation of other neurons by the advanced GABA release due to an early rapid [Ca] increase. CP-AMPARs have demonstrated a more pronounced impact on plasticity compared to NMDARs because of their capacity to elevate intracellular Ca levels independently of voltage. GABAergic neurons that express CP-AMPARs contribute to the disinhibition of glutamatergic neurons by suppressing GABAergic neurons that express CP-KARs. Hence, the presence of glutamate CP-KARs and CP-AMPARs is crucial in governing hyperexcitation and synaptic plasticity in GABAergic neurons.
PubMed: 38737208
DOI: 10.1007/s12551-024-01184-8 -
The Journal of Neuroscience : the... Jul 2023The rod photoreceptor synapse is the first synapse of dim-light vision and one of the most complex in the mammalian CNS. The components of its unique structure, a...
The rod photoreceptor synapse is the first synapse of dim-light vision and one of the most complex in the mammalian CNS. The components of its unique structure, a presynaptic ribbon and a single synaptic invagination enclosing several postsynaptic processes, have been identified, but disagreements about their organization remain. Here, we have used EM tomography to generate high-resolution images of 3-D volumes of the rod synapse from the female domestic cat. We have resolved the synaptic ribbon as a single structure, with a single arciform density, indicating the presence of one long site of transmitter release. The organization of the postsynaptic processes, which has been difficult to resolve with past methods, appears as a tetrad arrangement of two horizontal cell and two rod bipolar cell processes. Retinal detachment severely disrupts this organization. After 7 d, EM tomography reveals withdrawal of rod bipolar dendrites from most spherules; fragmentation of synaptic ribbons, which lose their tight association with the presynaptic membrane; and loss of the highly branched telodendria of the horizontal cell axon terminals. After detachment, the hilus, the opening through which postsynaptic processes enter the invagination, enlarges, exposing the normally sequestered environment within the invagination to the extracellular space of the outer plexiform layer. Our use of EM tomography provides the most accurate description to date of the complex rod synapse and details changes it undergoes during outer segment degeneration. These changes would be expected to disrupt the flow of information in the rod pathway. Ribbon-type synapses transmit the first electrical signals of vision and hearing. Despite their crucial role in sensory physiology, the three-dimensional ultrastructure of these synapses, especially the complex organization of the rod photoreceptor synapse, is not well understood. We used EM tomography to obtain 3-D imaging at nanoscale resolution to help resolve the organization of rod synapses in normal and detached retinas. This approach has enabled us to show that in the normal retina a single ribbon and arciform density oppose a tetrad of postsynaptic processes. In addition, it enabled us to provide a 3-D perspective of the ultrastructural changes that occur in response to retinal detachment.
Topics: Female; Animals; Cats; Retinal Detachment; Microscopy, Electron; Synapses; Retina; Retinal Bipolar Cells; Retinal Rod Photoreceptor Cells; Mammals
PubMed: 37414561
DOI: 10.1523/JNEUROSCI.2267-22.2023