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ACS Omega May 2024Maternal separation (MS) represents a profound early life stressor with enduring impacts on neuronal development and adult cognitive function in both humans and rodents....
Maternal separation (MS) represents a profound early life stressor with enduring impacts on neuronal development and adult cognitive function in both humans and rodents. MS is associated with persistent dysregulations in neurotransmitter systems, including the serotonin (5-HT) pathway, which is pivotal for mood stabilization and stress-coping mechanisms. Although the novel cannabinoid receptor, GPR55, is recognized for its influence on learning and memory, its implications on the function and synaptic dynamics of 5-HT neurons within the dorsal raphe nucleus (DRN) remain to be elucidated. In this study, we sought to discern the repercussions of GPR55 activation on 5-HT synthesis within the DRN of adult C57BL/6J mice that experienced MS. Concurrently, we analyzed potential alterations in excitatory synaptic transmission, long-term synaptic plasticity, and relevant learning and memory outcomes. Our behavioral assessments indicated a marked amelioration in MS-induced learning and memory deficits following GPR55 activation. In conjunction with this, we noted a substantial decrease in 5-HT levels in the MS model, while GPR55 activation stimulated tryptophan hydroxylase 2 synthesis and fostered the release of 5-HT. Electrophysiological patch-clamp analyses highlighted the ability of GPR55 activation to alleviate MS-induced cognitive deficits by modulating the frequency and magnitude of miniature excitatory postsynaptic currents within the DRN. Notably, this cognitive enhancement was underpinned by the phosphorylation of both NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In summary, our findings underscore the capacity of GPR55 to elevate 5-HT synthesis and modify synaptic transmissions within the DRN of juvenile mice, positing GPR55 as a promising therapeutic avenue for ameliorating MS-induced cognitive impairment.
PubMed: 38799363
DOI: 10.1021/acsomega.3c08934 -
Frontiers in Synaptic Neuroscience 2024Palmitoylation and depalmitoylation represent dichotomic processes by which a labile posttranslational lipid modification regulates protein trafficking and degradation....
Palmitoylation and depalmitoylation represent dichotomic processes by which a labile posttranslational lipid modification regulates protein trafficking and degradation. The depalmitoylating enzyme, palmitoyl-protein thioesterase 1 (PPT1), is associated with the devastating pediatric neurodegenerative condition, infantile neuronal ceroid lipofuscinosis (CLN1). CLN1 is characterized by the accumulation of autofluorescent lysosomal storage material (AFSM) in neurons and robust neuroinflammation. Converging lines of evidence suggest that in addition to cellular waste accumulation, the symptomology of CLN1 corresponds with disruption of synaptic processes. Indeed, loss of Ppt1 function in cortical neurons dysregulates the synaptic incorporation of the GluA1 AMPA receptor (AMPAR) subunit during a type of synaptic plasticity called synaptic scaling. However, the mechanisms causing this aberration are unknown. Here, we used the mouse model (both sexes) to further investigate how Ppt1 regulates synaptic plasticity and how its disruption affects downstream signaling pathways. To this end, we performed a palmitoyl-proteomic screen, which provoked the discovery that Akap5 is excessively palmitoylated at synapses. Extending our previous data, induction of synaptic scaling, which is regulated by Akap5, caused an excessive upregulation of GluA1 in mice. This synaptic change was associated with exacerbated disease pathology. Furthermore, the Akap5- and inflammation-associated transcriptional regulator, nuclear factor of activated T cells (NFAT), was sensitized in cortical neurons. Suppressing the upstream regulator of NFAT activation, calcineurin, with the FDA-approved therapeutic FK506 (Tacrolimus) modestly improved neuroinflammation in mice. These findings indicate that the absence of depalmitoylation stifles synaptic protein trafficking and contributes to neuroinflammation via an Akap5-associated mechanism.
PubMed: 38798824
DOI: 10.3389/fnsyn.2024.1384625 -
BioRxiv : the Preprint Server For... May 2024RNA editing is a post-transcriptional source of protein diversity and occurs across the animal kingdom. Given the complete profile of mRNA targets and their editing rate...
RNA editing is a post-transcriptional source of protein diversity and occurs across the animal kingdom. Given the complete profile of mRNA targets and their editing rate in individual cells is unclear, we analyzed single cell RNA transcriptomes from larval tonic and phasic glutamatergic motoneuron subtypes to determine the most highly edited targets and identify cell-type specific editing. From ∼15,000 genes encoded in the genome, 316 high confidence A-to-I canonical RNA edit sites were identified, with 102 causing missense amino acid changes in proteins regulating membrane excitability, synaptic transmission, and cellular function. Some sites showed 100% editing in single neurons as observed with mRNAs encoding mammalian AMPA receptors. However, most sites were edited at lower levels and generated variable expression of edited and unedited mRNAs within individual neurons. Together, these data provide insights into how the RNA editing landscape alters protein function to modulate the properties of two well-characterized neuronal populations in .
PubMed: 38798345
DOI: 10.1101/2024.05.17.594696 -
Life (Basel, Switzerland) May 2024Familial Alzheimer's disease (FAD) can be caused by mutations in that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor...
Familial Alzheimer's disease (FAD) can be caused by mutations in that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess the early calcium and glutamate phenotypes of FAD by measuring the Ca response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA, and kainate compared to isogenic control and healthy lines. The data show that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca responses to glutamate and AMPA, but not NMDA or kainate. Together, this suggests that mutations alter Ca and glutamate signaling as an early phenotype of FAD.
PubMed: 38792645
DOI: 10.3390/life14050625 -
Frontiers in Molecular Neuroscience 2024Functions of the cerebellar cortex, from motor learning to emotion and cognition, depend on the appropriate molecular composition at diverse synapse types. Glutamate...
Functions of the cerebellar cortex, from motor learning to emotion and cognition, depend on the appropriate molecular composition at diverse synapse types. Glutamate receptor distributions have been partially mapped using immunogold electron microscopy. However, information is lacking on the distribution of many other components, such as Shank2, a postsynaptic scaffolding protein whose cerebellar dysfunction is associated with autism spectrum disorders. Here, we used an adapted Magnified Analysis of the Proteome, an expansion microscopy approach, to map multiple glutamate receptors, scaffolding and signaling proteins at single synapse resolution in the cerebellar cortex. Multiple distinct synapse-selective distribution patterns were observed. For example, AMPA receptors were most concentrated at synapses on molecular layer interneurons and at climbing fiber synapses, Shank1 was most concentrated at parallel fiber synapses on Purkinje cells, and Shank2 at both climbing fiber and parallel fiber synapses on Purkinje cells but little on molecular layer interneurons. Our results are consistent with gene expression data but also reveal input-selective targeting within Purkinje cells. In specialized glomerular structures of the granule cell layer, AMPA receptors as well as most other synaptic components preferentially targeted to synapses. However, NMDA receptors and the synaptic GTPase activating protein SynGAP preferentially targeted to extrasynaptic sites. Thus, glomeruli may be considered integrative signaling units through which mossy fibers differentially activate synaptic AMPA and extrasynaptic NMDA receptor complexes. Furthermore, we observed NMDA receptors and SynGAP at adherens junctions, suggesting a role in structural plasticity of glomeruli. Altogether, these data contribute to mapping the cerebellar 'synaptome'.
PubMed: 38783902
DOI: 10.3389/fnmol.2024.1381534 -
Molecular Pain 2024Recent studies using different experimental approaches demonstrate that silent synapses may exist in the adult cortex including the sensory cortex and anterior cingulate...
Recent studies using different experimental approaches demonstrate that silent synapses may exist in the adult cortex including the sensory cortex and anterior cingulate cortex (ACC). The postsynaptic form of long-term potentiation (LTP) in the ACC recruits some of these silent synapses and the activity of calcium-stimulated adenylyl cyclases (ACs) is required for such recruitment. It is unknown if the chemical activation of ACs may recruit silent synapses. In this study, we found that activation of ACs contributed to synaptic potentiation in the ACC of adult mice. Forskolin, a selective activator of ACs, recruited silent responses in the ACC of adult mice. The recruitment was long-lasting. Interestingly, the effect of forskolin was not universal, some silent synapses did not undergo potentiation or recruitment. These findings suggest that these adult cortical synapses are not homogenous. The application of a selective calcium-permeable AMPA receptor inhibitor 1-naphthyl acetyl spermine (NASPM) reversed the potentiation and the recruitment of silent responses, indicating that the AMPA receptor is required. Our results strongly suggest that the AC-dependent postsynaptic AMPA receptor contributes to the recruitment of silent responses at cortical LTP.
Topics: Animals; Mice; Gyrus Cinguli; Colforsin; Long-Term Potentiation; Adenylyl Cyclases; Male; Receptors, AMPA; Mice, Inbred C57BL; Synapses; Calcium
PubMed: 38744422
DOI: 10.1177/17448069241258110 -
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 -
Brain Research May 2024Although the focal brain cooling technique is widely used to examine brain function, the effects of cortical temperature at various levels on sensory information...
Although the focal brain cooling technique is widely used to examine brain function, the effects of cortical temperature at various levels on sensory information processing and neural mechanisms remain underexplored. To elucidate the mechanisms of temperature modulation in somatosensory processing, this study aimed to examine how P1 and N1 deflections of somatosensory evoked potentials (SEPs) depend on cortical temperature and how excitatory and inhibitory inputs contribute to this temperature dependency. SEPs were generated through electrical stimulation of the contralateral forepaw in anesthetized rats. The SEPs were recorded while cortical temperatures were altered between 17-38 °C either without any antagonists, with a gamma-aminobutyric acid type A (GABA) receptor antagonist (gabazine), with aminomethylphosphonic acid (AMPA) receptor antagonist (NBQX), or with N-Methyl-D-aspartic acid (NMDA) receptor antagonist ([R]-CPP). The effects of different gabazine concentrations (0, 1, and 10 µM) were examined in the 35-38 °C range. The P1/N1 amplitudes and their peak-to-peak differences plotted against cortical temperature showed an inverted U relationship with a maximum at approximately 27.5 °C when no antagonists were administered. The negative correlation between these amplitudes and temperatures of ≥ 27.5 °C plateaued after gabazine administration, which occurred progressively as the gabazine concentration increased. In contrast, the correlation remained negative after the administration of NBQX and (R)-CPP. These results suggest that GABAergic inhibitory inputs contribute to the negative correlation between SEP amplitude and cortical temperature around the physiological cortical temperature.
PubMed: 38735427
DOI: 10.1016/j.brainres.2024.148995 -
Neurology(R) Neuroimmunology &... Jul 2024We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of...
OBJECTIVES
We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as an important finding.
METHODS
This is a case report from a Dutch academic hospital. Repeated clinical examinations, repeated brain MRI and extended diagnostics on serum and CSF were performed. We used the CARE checklist.
RESULTS
A 7-year-old boy was diagnosed with CTLA-4h based on family screening. On diagnosis, he had mild chronic diarrhea and autism spectrum disorder, but no abnormalities in extensive laboratory screening. Six months later, he presented with sudden-onset autoimmune encephalitis. Repeated brain MRI revealed no abnormalities, but immunohistochemistry analysis on serum and CSF showed the presence of AMPAR antibodies. Treatment was initially focused on immunomodulation and targeted CTLA-4 replacement therapy. Because of the persistent fluctuating cerebellar and neuropsychiatric symptoms and the potential clinical significance of the AMPAR antibodies, treatment was intensified with repetition of first-line immunomodulation and rituximab. This combined therapy resulted in sustained clinical improvement and served as a bridge to curative hematopoietic stem cell transplantation.
DISCUSSION
This case illustrates the rare early onset of autoimmune encephalitis and presence of AMPAR antibodies in CTLA-4h. Targeted CTLA-4 replacement therapy resulted in a partial response. However, awaiting its optimal therapeutic effect, refractory CNS symptoms required intensification of immunomodulation. The identification of AMPAR antibodies guided our treatment decisions.
CLASSIFICATION OF EVIDENCE
This provides Class IV evidence. It is a single observational study without controls.
Topics: Humans; Male; Child; CTLA-4 Antigen; Encephalitis; Hashimoto Disease; Autoantibodies; Receptors, AMPA; Haploinsufficiency; Rituximab; Immunologic Factors
PubMed: 38728609
DOI: 10.1212/NXI.0000000000200254 -
Frontiers in Neural Circuits 2024A morphologically present but non-functioning synapse is termed a silent synapse. Silent synapses are categorized into "postsynaptically silent synapses," where AMPA...
A morphologically present but non-functioning synapse is termed a silent synapse. Silent synapses are categorized into "postsynaptically silent synapses," where AMPA receptors are either absent or non-functional, and "presynaptically silent synapses," where neurotransmitters cannot be released from nerve terminals. The presence of presynaptically silent synapses remains enigmatic, and their physiological significance is highly intriguing. In this study, we examined the distribution and developmental changes of presynaptically active and silent synapses in individual neurons. Our findings show a gradual increase in the number of excitatory synapses, along with a corresponding decrease in the percentage of presynaptically silent synapses during neuronal development. To pinpoint the distribution of presynaptically active and silent synapses, i.e., their positional information, we employed Sholl analysis. Our results indicate that the distribution of presynaptically silent synapses within a single neuron does not exhibit a distinct pattern during synapse development in different distance from the cell body. However, irrespective of neuronal development, the proportion of presynaptically silent synapses tends to rise as the projection site moves farther from the cell body, suggesting that synapses near the cell body may exhibit higher synaptic transmission efficiency. This study represents the first observation of changes in the distribution of presynaptically active and silent synapses within a single neuron.
Topics: Animals; Hippocampus; Neurons; Synapses; Cells, Cultured; Presynaptic Terminals; Excitatory Postsynaptic Potentials; Rats; Synaptic Transmission
PubMed: 38715983
DOI: 10.3389/fncir.2024.1358570