Neuronal Synaptic Plasticity Research Articles

CNS/PNS proteoglycans functionalize neuronal and astrocyte niche microenvironments optimizing cellular activity by preserving membrane polarization dynamics, ionic microenvironments, ion fluxes, neuronal activation, and network neurotransductive capacity.

Central and peripheral nervous system (CNS/PNS) proteoglycans (PGs) have diverse functional roles, this study examined how these control cellular behavior and tissue function. The CNS/PNS extracellular matrix (ECM) is a dynamic, responsive, highly interactive, space-filling, cell supportive, stabilizing structure maintaining tissue compartments, ionic microenvironments, and microgradients that regulate neuronal activity and maintain the neuron in an optimal ionic microenvironment. The CNS/PNS contains a high glycosaminoglycan content (60% hyaluronan, HA) and a diverse range of stabilizing PGs. Immobilization of HA in brain tissues by HA interactive hyalectan PGs preserves tissue hydration and neuronal activity, a paucity of HA in brain tissues results in a pro-convulsant epileptic phenotype. Diverse CS, KS, and HSPGs stabilize the blood-brain barrier and neurovascular unit, provide smart gel neurotransmitter neuron vesicle storage and delivery, organize the neuromuscular junction basement membrane, and provide motor neuron synaptic plasticity, and photoreceptor and neuron synaptic functions. PG-HA networks maintain ionic fluxes and microgradients and tissue compartments that contribute to membrane polarization dynamics essential to neuronal activation and neurotransduction. Hyalectans form neuroprotective perineuronal nets contributing to synaptic plasticity, memory, and cognitive learning. Sialoglycoprotein associated with cones and rods (SPACRCAN), an HA binding CSPG, stabilizes the inter-photoreceptor ECM. HSPGs pikachurin and eyes shut stabilize the photoreceptor synapse aiding in phototransduction and neurotransduction with retinal bipolar neurons crucial to visual acuity. This is achieved through Laminin G motifs in pikachurin, eyes shut, and neurexins that interact with the dystroglycan-cytoskeleton-ECM-stabilizing synaptic interconnections, neuronal interactive specificity, and co-ordination of regulatory action potentials in neural networks.

Role of ACSBG1 in brain lipid metabolism and X-linked adrenoleukodystrophy pathogenesis: Insights from a knockout mouse model.

The "bubblegum" acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during the development of the mouse brain, facilitating the activation of long-chain fatty acids (LCFAs) and their integration into essential lipid species crucial for brain function. Through its enzymatic activity, ACSBG1 converts LCFAs into acyl-CoA derivatives, supporting vital processes like membrane formation, myelination, and energy production. Its regulatory role significantly influences neuronal growth, synaptic plasticity, and overall brain development, highlighting its importance in maintaining lipid homeostasis and proper brain function. Originally discovered in the fruit fly brain, ACSBG1 attracted attention for its potential implication in X-linked adrenoleukodystrophy (XALD) pathogenesis. Studies using Drosophila melanogaster lacking the ACSBG1 homolog, bubblegum, revealed adult neurodegeneration with elevated levels of very long-chain fatty acids (VLCFA). To explore ACSBG1's role in fatty acid (FA) metabolism and its relevance to XALD, we created an ACSBG1 knockout (Acsbg1-/-) mouse model and examined its impact on lipid metabolism during mouse brain development. Phenotypically, Acsbg1-/- mice resembled wild type (w.t.) mice. Despite its primary expression in tissues affected by XALD, brain, adrenal gland and testis, ACSBG1 depletion did not significantly reduce total ACS enzyme activity in these tissues when using LCFA or VLCFA as substrates. However, analysis unveiled intriguing developmental and compositional changes in FA levels associated with ACSBG1 deficiency. In the adult mouse brain, ACSBG1 expression peaked in the cerebellum, with lower levels observed in other brain regions. Developmentally, ACSBG1 expression in the cerebellum was initially low during the first week of life but increased dramatically thereafter. Cerebellar FA levels were assessed in both w.t. and Acsbg1-/- mouse brains throughout development, revealing notable differences. While saturated VLCFA levels were typically high in XALD tissues and in fruit flies lacking ACSBG1, cerebella from Acsbg1-/- mice displayed lower saturated VLCFA levels, especially after about 8 days of age. Additionally, monounsaturated ω9 FA levels exhibited a similar trend as saturated VLCFA, while ω3 polyunsaturated FA levels were elevated in Acsbg1-/- mice. Further analysis of specific FA levels provided additional insights into potential roles for ACSBG1. Notably, the decreased VLCFA levels in Acsbg1-/- mice primarily stemmed from changes in C24:0 and C26:0, while reduced ω9 FA levels were mainly observed in C18:1 and C24:1. ACSBG1 depletion had minimal effects on saturated long-chain FA or ω6 polyunsaturated FA levels but led to significant increases in specific ω3 FA, such as C20:5 and C22:5. Moreover, the impact of ACSBG1 deficiency on the developmental expression of several cerebellar FA metabolism enzymes, including those required for synthesis of ω3 polyunsaturated FA, was assessed; these FA can potentially be converted into bioactive signaling molecules like eicosanoids and docosanoids. In conclusion, despite compelling circumstantial evidence, it is unlikely that ACSBG1 directly contributes to the pathology of XALD. Instead, the effects of ACSBG1 knockout on processes regulated by eicosanoids and/or docosanoids should be further investigated.

Regional-specific changes in rat brain BDNF in a model of methamphetamine abuse

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays key roles in neuronal protection and synaptic plasticity. Changes in BDNF are associated with various pathological conditions, including methamphetamine (meth) addiction, although the effects of meth on BDNF expression are not always consistent. We have previously demonstrated region-specific effects of a chronic meth regime on BDNF methylation and expression in the rat brain. This study aims to determine the effect of chronic meth administration on the expression of BDNF protein using immunohistochemistry in the rat frontal cortex and hippocampus. Novel object recognition (NOR) as a measure of cognitive function was also determined. Male Sprague Dawley rats were administered a chronic escalating dose (0.1–4 mg/kg over 14 days) (ED) of meth or vehicle; a subgroup of animals receiving meth were also given an acute “binge” (4x6mg) dose on the final day before NOR testing. The results showed that hippocampal CA1 BDNF protein was significantly increased by 72 % above control values in the ED-binge rats, while other hippocampal regions and frontal cortex were not significantly affected. Meth-administered animals also demonstrated deficits in NOR after 24 h delay. No significant effect of the additional binge dose on BDNF protein or NOR findings was apparent. This finding is consistent with our previous results of reduced DNA methylation and increased expression of the BDNF gene in this region. The hippocampal BDNF increase may reflect an initial increase in a protective factor produced in response to elevated glutamate release resulting in neurodegenerative excitotoxicity.

Effects of Kv1.3 knockout on pyramidal neuron excitability and synaptic plasticity in piriform cortex of mice.

Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of neuropsychiatric disorders. Kv1.3 is highly expressed in the olfactory bulb and piriform cortex and involved in the process of odor perception and nutrient metabolism in animals. Previous studies have explored the function of Kv1.3 in olfactory bulb, while the role of Kv1.3 in piriform cortex was less known. In this study, we investigated the neuronal changes of piriform cortex and feeding behavior after smell stimulation, thus revealing a link between the olfactory sensation and body weight in Kv1.3 KO mice. Coronal slices including the anterior piriform cortex were prepared, whole-cell recording and Ca2+ imaging of pyramidal neurons were conducted. We showed that the firing frequency evoked by depolarization pulses and Ca2+ influx evoked by high K+ solution were significantly increased in pyramidal neurons of Kv1.3 knockout (KO) mice compared to WT mice. Western blotting and immunofluorescence analyses revealed that the downstream signaling molecules CaMKII and PKCα were activated in piriform cortex of Kv1.3 KO mice. Pyramidal neurons in Kv1.3 KO mice exhibited significantly reduced paired-pulse ratio and increased presynaptic Cav2.1 expression, proving that the presynaptic vesicle release might be elevated by Ca2+ influx. Using Golgi staining, we found significantly increased dendritic spine density of pyramidal neurons in Kv1.3 KO mice, supporting the stronger postsynaptic responses in these neurons. In olfactory recognition and feeding behavior tests, we showed that Kv1.3 conditional knockout or cannula injection of 5-(4-phenoxybutoxy) psoralen, a Kv1.3 channel blocker, in piriform cortex both elevated the olfactory recognition index and altered the feeding behavior in mice. In summary, Kv1.3 is a key molecule in regulating neuronal activity of the piriform cortex, which may lay a foundation for the treatment of diseases related to piriform cortex and olfactory detection.

Association between Rhabdomyolysis and RHOBTB2 Encephalopathy

First described in 2018, heterozygous variants of the RHOBTB2 gene, affect the translation of a Rho GTPase protein, essential in neuronal development and synaptic plasticity. The few cases described are characterized by a clinical spectrum of epileptic encephalopathy, psychomotor and cognitive delay, microcephaly, nonspecific facial dysmorphism and movement disorder. We report a case of a female child, who had two seizures at 28 days of age. She exhibited a normal psychomotor development, until she had another seizure at 6 months, after which she started showing a movement disorder, followed by impair- ment of psychomotor development. Amongst the multiple hospitalizations, one of them was due to status epilepticus with severe rhabdomyolysis. At the age of 7, by ex- ome sequencing, a de novo pathogenic variant was identified in the RHOBTB2 gene. Although the main characteristics of this syndrome have been described in previous studies, its possible relation with rhabdomyolysis has never been reported.

Research progress on the mechanism of acupuncture treatment for vascular dementia

Acupuncture can intervene with and treat vascular dementia (VD) through multiple targets and pathways. The mechanisms of its action involve inhibiting central inflammatory responses, regulating neuronal synaptic plasticity, modulating oxidative stress, reducing neuronal apoptosis, and adjusting cellular autophagy. This paper summarizes researches on the mechanisms of acupuncture treatment for VD over the past decade, aiming to provide theoretical support for the clinical application of acupuncture in treating VD and offer a reference for future in-depth research in this field.

Exploring the role of eosinophil cationic protein (ECP) in schizophrenia: Insights and implications.

Schizophrenia, a multifaceted neuropsychiatric disorder characterized by disruptions in perception, cognition, and behavior, has been associated with neuroinflammatory processes. Emerging research has increasingly recognized the potential involvement of immune-related factors in the pathogenesis of schizophrenia, prompting investigations into biomarkers associated with inflammatory cascades. Among these biomarkers, Eosinophil Cationic Protein (ECP), traditionally known for its role in eosinophil-mediated immune responses, has garnered attention for its putative association with neuroinflammation in schizophrenia. This paper critically examines the current understanding of the role of ECP in schizophrenia. ECP, a cytotoxic protein released by eosinophils, has diverse immunomodulatory effects and has been identified in altered concentrations in individuals with schizophrenia. Studies have reported elevated levels of ECP in peripheral fluids of schizophrenia patients, suggesting a possible link between ECP dysregulation and the inflammatory milieu characteristic of the disorder. Moreover, the potential implications of ECP in neuroinflammatory processes relevant to schizophrenia pathophysiology are discussed. ECP's role in modulating immune responses and its potential impact on neuronal function, synaptic plasticity, and neurotoxicity within the central nervous system (CNS) are considered, highlighting the potential contribution of ECP to the neuroinflammatory mechanisms underlying schizophrenia. In conclusion, while the precise role of ECP in schizophrenia pathogenesis warrants further elucidation, exploring its association with neuroinflammation holds promise in unraveling new biomarkers and therapeutic avenues for managing this complex psychiatric disorder.

Research progress of acupuncture regulating ERK signaling pathway in the treatment of depression.

Acupuncture treatment for depression has definite therapeutic efficacy, and its mechanism has been extensively studied. The extracellular regulatory protein kinase(ERK) signaling pathway is involved in the development and progression of depression. This article reviewed and summarized the research progress on the regulation of the ERK signaling pathway by acupuncture in the treatment of depression in recent years, focusing on the physiological activation and regulatory mechanism of the ERK signaling pathway, its association with the occurrence of depression, and the mechanisms through which acupuncture activates the ERK signaling pathway to treat depression (including enhancing neuronal synaptic plasticity, promoting the release of neurotrophic factors, and inhibiting neuronal apoptosis). Future research could explore the relationship between the ERK pathway and other pathways, investigate other brain regions besides the prefrontal cortex and hippocampus, examine differences in regulatory mechanisms between male and female patients, assess the effects of different acupuncture techniques on the ERK pathway, and increase efforts to explore mechanism of synaptic plasticity regulation, so as to provide reference for the clinical application and mechanism sludy of acupuncture in depression treatment.

Kainate receptor channel opening and gating mechanism

Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission1–4. Kainate receptors modulate neuronal circuits and synaptic plasticity during the development and function of the central nervous system and are implicated in various neurological and psychiatric diseases, including epilepsy, depression, schizophrenia, anxiety and autism5–11. Although structures of kainate receptor domains and subunit assemblies are available12–18, the mechanism of kainate receptor gating remains poorly understood. Here we present cryo-electron microscopy structures of the kainate receptor GluK2 in the presence of the agonist glutamate and the positive allosteric modulators lectin concanavalin A and BPAM344. Concanavalin A and BPAM344 inhibit kainate receptor desensitization and prolong activation by acting as a spacer between the amino-terminal and ligand-binding domains and a stabilizer of the ligand-binding domain dimer interface, respectively. Channel opening involves the kinking of all four pore-forming M3 helices. Our structures reveal the molecular basis of kainate receptor gating, which could guide the development of drugs for treatment of neurological disorders.

Repeated mild traumatic brain injury in the parietal cortex inhibits expressions of NLG-1 and PSD-95 in the medulla oblongata of mice

To assess the effects of repeated mild traumatic brain injury (rmTBI) in the parietal cortex on neuronal morphology and synaptic plasticity in the medulla oblongata of mice. Thirty-two male ICR mice were randomly divided into sham operation group (n=8) and rmTBI group (n=24). The mice in the latter group were subjected to repeated mild impact injury of the parietal cortex by a free-falling object. The mice surviving the injuries were evaluated for neurological deficits using neurological severity scores (NSS), righting reflex test and forced swimming test, and pathological changes of the neuronal cells in the medulla oblongata were observed with HE and Nissl staining. Western blotting and immunofluorescence staining were used to detect the expressions of neuroligin 1(NLG-1) and postsynaptic density protein 95(PSD-95) in the medulla oblongata of the mice that either survived rmTBI or not. None of the mice in the sham-operated group died, while the mortality rate was 41.67% in rmTBI group. The mice surviving rmTBI showed significantly reduced NSS, delayed recovery of righting reflex, increased immobility time in forced swimming test (P < 0.05), and loss of Nissl bodies; swelling and necrosis were observed in a large number of neurons in the medulla oblongata, where the expression levels of NLG-1 and PSD-95 were significantly downregulated (P < 0.05). The mice that did not survive rmTBI showed distorted and swelling nerve fibers and decreased density of neurons in the medulla oblongina with lowered expression levels of NLG-1 and PSD-95 compared with the mice surviving the injuries (P < 0.01). The structural and functional anomalies of the synapses in the medulla oblongata may contribute to death and neurological impairment following rmTBI in mice.

Melatonin Ameliorates Post-Stroke Cognitive Impairment in Mice by Inhibiting Excessive Mitophagy.

Post-stroke cognitive impairment (PSCI) remains the most common consequence of ischemic stroke. In this study, we aimed to investigate the role and mechanisms of melatonin (MT) in improving cognitive dysfunction in stroke mice. We used CoCl2-induced hypoxia-injured SH-SY5Y cells as a cellular model of stroke and photothrombotic-induced ischemic stroke mice as an animal model. We found that the stroke-induced upregulation of mitophagy, apoptosis, and neuronal synaptic plasticity was impaired both in vivo and in vitro. The results of the novel object recognition test and Y-maze showed significant cognitive deficits in the stroke mice, and Nissl staining showed a loss of neurons in the stroke mice. In contrast, MT inhibited excessive mitophagy both in vivo and in vitro and decreased the levels of mitophagy proteins PINK1 and Parkin, and immunofluorescence staining showed reduced co-localization of Tom20 and LC3. A significant inhibition of mitophagy levels could be directly observed under transmission electron microscopy. Furthermore, behavioral experiments and Nissl staining showed that MT ameliorated cognitive deficits and reduced neuronal loss in mice following a stroke. Our results demonstrated that MT inhibits excessive mitophagy and improves PSCI. These findings highlight the potential of MT as a preventive drug for PSCI, offering promising therapeutic implications.

Distinct calcium sources regulate temporal profiles of NMDAR and mGluR-mediated protein synthesis.

Calcium signaling is integral for neuronal activity and synaptic plasticity. We demonstrate that the calcium response generated by different sources modulates neuronal activity-mediated protein synthesis, another process essential for synaptic plasticity. Stimulation of NMDARs generates a protein synthesis response involving three phases-increased translation inhibition, followed by a decrease in translation inhibition, and increased translation activation. We show that these phases are linked to NMDAR-mediated calcium response. Calcium influx through NMDARs elicits increased translation inhibition, which is necessary for the successive phases. Calcium through L-VGCCs acts as a switch from translation inhibition to the activation phase. NMDAR-mediated translation activation requires the contribution of L-VGCCs, RyRs, and SOCE. Furthermore, we show that IP3-mediated calcium release and SOCE are essential for mGluR-mediated translation up-regulation. Finally, we signify the relevance of our findings in the context of Alzheimer's disease. Using neurons derived from human fAD iPSCs and transgenic AD mice, we demonstrate the dysregulation of NMDAR-mediated calcium and translation response. Our study highlights the complex interplay between calcium signaling and protein synthesis, and its implications in neurodegeneration.

Astrocytic GDNF ameliorates anesthesia and surgery-induced cognitive impairment by promoting hippocampal synaptic plasticity in aged mice

BackgroundPerioperative neurocognitive disorders (PND) are common complications after surgery in older patients. However, the specific mechanism of this condition remains unclear. Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophin that abundantly expressed throughout the brain. It can enhance synaptic plasticity and alleviate learning and memory impairments. Thus, the purpose of this study was to investigate the role of GDNF in PND and the mechanisms involved. MethodsThe PND animal model was established by performing left tibial fracture surgery on 18-month-old C57BL/6 mice under sevoflurane anesthesia. Recombinant adeno-associated virus (rAAV)-GDNF or empty vectors were injected bilaterally into the hippocampal CA1 region of aged mice 3 weeks before anesthesia/surgery. The open field and fear conditioning test were used to assess the behavior changes. Golgi staining and electrophysiology were utilized to evaluate the morphological and functional alterations of neuronal synaptic plasticity. Western blot analysis was carried out to measure the proteins expression levels and immunofluorescence staining was performed to probe the cellular localization of GDNF. ResultsMice with surgery and anesthesia showed a significant decrease in hippocampus-dependent learning and memory, accompanied by a decline in hippocampal synaptic plasticity. Anesthesia/surgery induced a reduction of GDNF, which was colocalized with astrocytes. Overexpression of GDNF in astrocytes could ameliorate the decline in cognitive function by improving hippocampal synaptic plasticity, meanwhile astrocytic GDNF rescued the anesthesia/surgery-induced decrease in GFRα1 and NCAM. ConclusionThe study concludes that astrocytic GDNF may improve anesthesia/surgery-induced cognitive impairment by promoting hippocampal synaptic plasticity in aged mice via the GFRα1/NCAM pathway.

Environmental enrichment alleviates hyperalgesia by modulating central sensitization in a nitroglycerin-induced chronic migraine model of mice

BackgroundChronic migraine (CM) is a debilitating neurofunctional disorder primarily affecting females, characterized by central sensitization. Central sensitization refers to the enhanced response to sensory stimulation, which involves changes in neuronal excitability, synaptic plasticity, and neurotransmitter release. Environmental enrichment (EE) can increase the movement, exploration, socialization and other behaviors of mice. EE has shown promising effects in various neurological disorders, but its impact on CM and the underlying mechanism remains poorly understood. Therefore, the purpose of this study was to determine whether EE has the potential to serve as a cost-effective intervention strategy for CM.MethodsA mouse CM model was successfully established by repeated administration of nitroglycerin (NTG). We selected adult female mice around 8 weeks old, exposed them to EE for 2 months, and then induced the CM model. Nociceptive threshold tests were measured using Von Frey filaments and a hot plate. The expression of c-Fos, calcitonin gene-related peptide (CGRP) and inflammatory response were measured using WB and immunofluorescence to evaluate central sensitization. RNA sequencing was used to find differentially expressed genes and signaling pathways. Finally, the expression of the target differential gene was investigated.ResultsRepeated administration of NTG can induce hyperalgesia in female mice and increase the expression of c-Fos and CGRP in the trigeminal nucleus caudalis (TNC). Early exposure of mice to EE reduced NTG-induced hyperalgesia in CM mice. WB and immunofluorescence revealed that EE inhibited the overexpression of c-Fos and CGRP in the TNC of CM mice and alleviated the inflammatory response of microglia activation. RNA sequencing analysis identified that several central sensitization-related signaling pathways were altered by EE. VGluT1, a key gene involved in behavior, internal stimulus response, and ion channel activity, was found to be downregulated in mice exposed to EE.ConclusionEE can significantly ameliorate hyperalgesia in the NTG-induced CM model. The mechanisms may be to modulate central sensitization by reducing the expression of CGRP, attenuating the inflammatory response, and downregulating the expression of VGluT1, etc., suggesting that EE can serve as an effective preventive strategy for CM.

Targeting brain‐derived neurotrophic factor in the treatment of neurodegenerative diseases: A review

AbstractNeurodegenerative diseases, marked by the gradual death of neurons, present a significant and growing public health challenge. Brain‐derived neurotrophic factor (BDNF) is crucial for the survival, development, and synaptic plasticity of neurons. Studies have consistently demonstrated that perturbed BDNF communication pathways are associated with the development and progression of neurodegenerative conditions, underscoring their potential as therapeutic targets. This review aimed to summarize the existing findings regarding BDNF expression, metabolism, and signaling transduction. Furthermore, we reviewed the intricate roles of BDNF signaling pathways in neurodegenerative diseases, elucidating their contributions to disease onset and progression. The latest advancements in targeting BDNF for the treatment of neurodegenerative diseases, including the development of small molecules, nucleic acid‐based therapeutics, and antibody‐based approaches, were also summarized. Despite recent strides, challenges persist, including a lack of comprehensive understanding of BDNF modulation across diverse neurodegenerative contexts and the absence of clinically approved BDNF‐targeted drugs.

Hippocampal proteome comparison of infant and adult Fmr1 deficiency mice reveals adult-related changes associated with postsynaptic density

Deficiency in fragile X mental retardation 1 (Fmr1) leads to loss of its encoded protein FMRP and causes fragile X syndrome (FXS) by dysregulating its target gene expression in an age-related fashion. Using comparative proteomic analysis, this study identified 105 differentially expressed proteins (DEPs) in the hippocampus of postnatal day 7 (P7) Fmr1−/y mice and 306 DEPs of P90 Fmr1−/y mice. We found that most DEPs in P90 hippocampus were not changed in P7 hippocampus upon FMRP absence, and some P90 DEPs exhibited diverse proteophenotypes with abnormal expression of protein isoform or allele variants. Bioinformatic analyses showed that the P7 DEPs were mainly enriched in fatty acid metabolism and oxidoreductase activity and nutrient responses; whereas the P90 PEPs (especially down-regulated DEPs) were primarily enriched in postsynaptic density (PSD), neuronal projection development and synaptic plasticity. Interestingly, 25 of 30 down-regulated PSD proteins present in the most enriched protein to protein interaction network, and 6 of them (ANK3, ATP2B2, DST, GRIN1, SHANK2 and SYNGAP1) are both FMRP targets and autism candidates. Therefore, this study suggests age-dependent alterations in hippocampal proteomes upon loss of FMRP that may be associated with the pathogenesis of FXS and its related disorders. SignificanceIt is well known that loss of FMRP resulted from Fmr1 deficiency leads to fragile X syndrome (FXS), a common neurodevelopmental disorder accompanied by intellectual disability and autism spectrum disorder (ASD). FMRP exhibits distinctly spatiotemporal patterns in the hippocampus between early development and adulthood, which lead to distinct dysregulations of gene expression upon loss of FMRP at the two age stages potentially linked to age-related phenotypes. Therefore, comparison of hippocampal proteomes between infancy and adulthood is valuable to provide insights into the early causations and adult-dependent consequences for FXS and ASD. Using a comparative proteomic analysis, this study identified 105 and 306 differentially expressed proteins (DEPs) in the hippocampi of postnatal day 7 (P7) and P90 Fmr1−/y mice, respectively. Few overlapping DEPs were identified between P7 and P90 stages, and the P7 DEPs were mainly enriched in the regulation of fatty acid metabolism and oxidoreduction, whereas the P90 DEPs were preferentially enriched in the regulation of synaptic formation and plasticity. Particularly, the up-regulated P90 proteins are primarily involved in immune responses and neurodegeneration, and the down-regulated P90 proteins are associated with postsynaptic density, neuron projection and synaptic plasticity. Our findings suggest that distinctly changed proteins in FMRP-absence hippocampus between infancy and adulthood may contribute to age-dependent pathogenesis of FXS and ASD.

Phrenic Motor Neuron Fractalkine Signaling to Nearby Microglia Regulates Phrenic Long-Term Facilitation

Although microglia are traditionally regarded as innate CNS immune cells, recent studies demonstrate that microglia also play key roles in normal CNS functions. For example, microglia engage in bidirectional communication with other cell types ( e.g., neurons) to regulate diverse processes including neuronal excitability, architecture and synaptic plasticity. Although neuron-microglia interactions regulate hippocampal synaptic plasticity, little is known concerning the role of microglia in regulating respiratory motor plasticity. One well-studied form of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a prolonged increase in phrenic motor output following acute intermittent hypoxia (AIH). Whereas AIH consisting of moderate hypoxic episodes (mAIH) elicits pLTF by a serotonin-dominant, adenosine-constrained mechanism, severe AIH (sAIH) elicits pLTF by an adenosine-dominant, serotonin-constrained mechanism. Neurons interact with microglia via release of fractalkine (CX3CL1), activating responses from nearby microglia, the only CNS cell-type known to express fractalkine receptors (CX3CR1). Cervical spinal fractalkine protein injections elicit phrenic motor facilitation similar to pLTF and trigger glial ATP/adenosine release, consistent with the hypothesis that neuronal fractalkine release during hypoxia elicits extracellular adenosine accumulation, thereby modulating AIH-induced pLTF. Here, we tested the hypothesis that phrenic motor neuron fractalkine protein underlies the adenosine-constraint to mAIH-induced pLTF, and drives sAIH-induced pLTF. In adult male Sprague Dawley rats, siRNA knockdown of phrenic motor neuron fractalkine mRNA and protein was achieved via intrapleural injections of siRNAs targeting fractalkine mRNA for 3 successive days. Fractalkine knock-down: 1) enhanced serotonin-dependent mAIH-induced pLTF (100±7%; n=6; vs controls: 50±5%; n=7; p&lt;0.001), but 2) attenuated adenosine-dependent, sAIH-induced pLTF (23±12%; n=5; vs controls: 88±7%; n=7; p=0.001). These findings suggest that hypoxia triggers dose-dependent phrenic motor neuron fractalkine release, activating CX3CR1 on nearby microglia. Subsequent microglial ATP release and conversion to adenosine activates phrenic motor neuron adenosine 2A receptors which: 1) undermines mAIH-induced (serotonin-dominant) pLTF; or 2) reaches levels suffcient to drive sAIH-induced (adenosine-dominant) pLTF. These findings increase our understanding of how spinal intercellular interactions regulate AIH-induced phrenic motor plasticity. NIH R01HL148030 (GSM), NIH R01HL149800 (GSM), NIH T32HL134621-5 (ABM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Analysis of mechanism of core points in acupuncture and moxibustion treatment for epilepsy based on data mining.

To explore the mechanism of core points in acupuncture and moxibustion treatment for epilepsy by using data mining technique, so as to provide a reference for clinical practice and experimental research. The data comes from relevant documents collected from CNKI, Wanfang, SinoMed, VIP, PubMed, Embase, Cochrane Library, EBSCO, Web of Science databases. The selected acupoints were analyzed in descriptive statistics, high-frequency acupoints group and core acupoint prescription. Further, potential target mining, "core acupoint prescription-target-epilepsy" network construction, protein-protein interactions (PPI) network establishment and core target extraction, gene ontology (GO) and KEGG gene enrichment analysis of the core acupoint prescription were carried out to predict its anti-epileptic potential mechanism. A total of 122 acupoint prescriptions were included. The core acupoint prescriptions were Baihui (GV20), Hegu (LI4), Neiguan (PC6), Shuigou (GV26) and Taichong (LR3). 277 potential targets were identified, among which 134 were shared with epilepsy. The core targets were extracted by PPI network topology analysis, including signal transducer and activator of transcription 3, tumor necrosis factor (TNF), interleukin (IL)-6, protein kinase B1, c-Jun N-terminal kinase, brain-derived neurotrophic factor, tumor protein 53, vascular endothelial growth factor A, Caspase-3, epidermal growth factor receptor, etc. The main anti-epileptic pathways of the core acupoints were predicted by KEGG enrichment, including lipid and atherosclerosis, neurodegeneration, phosphatidylinositol-3-kinase/protein B kinase signaling pathway, mitogen-activated protein kinase signaling pathway, cyclic adenosine monophosphate signaling pathway, TNF signaling pathway, IL-17 signaling pathway, hypoxia-inducible factor-1 signaling pathway, apoptosis, etc., involving neuronal death, synaptic plasticity, oxidative stress, inflammation and other related biological process. The core acupoint prescription of acupuncture and moxibustion intervention for epilepsy can act on multiple targets and multiple pathways to exert anti-epileptic effects, which can provide a theoretical basis for further clinical application and mechanism research.

SNP and Structural Study of the Notch Superfamily Provides Insights and Novel Pharmacological Targets against the CADASIL Syndrome and Neurodegenerative Diseases.

The evolutionary conserved Notch signaling pathway functions as a mediator of direct cell-cell communication between neighboring cells during development. Notch plays a crucial role in various fundamental biological processes in a wide range of tissues. Accordingly, the aberrant signaling of this pathway underlies multiple genetic pathologies such as developmental syndromes, congenital disorders, neurodegenerative diseases, and cancer. Over the last two decades, significant data have shown that the Notch signaling pathway displays a significant function in the mature brains of vertebrates and invertebrates beyond neuronal development and specification during embryonic development. Neuronal connection, synaptic plasticity, learning, and memory appear to be regulated by this pathway. Specific mutations in human Notch family proteins have been linked to several neurodegenerative diseases including Alzheimer's disease, CADASIL, and ischemic injury. Neurodegenerative diseases are incurable disorders of the central nervous system that cause the progressive degeneration and/or death of brain nerve cells, affecting both mental function and movement (ataxia). There is currently a lot of study being conducted to better understand the molecular mechanisms by which Notch plays an essential role in the mature brain. In this study, an in silico analysis of polymorphisms and mutations in human Notch family members that lead to neurodegenerative diseases was performed in order to investigate the correlations among Notch family proteins and neurodegenerative diseases. Particular emphasis was placed on the study of mutations in the Notch3 protein and the structure analysis of the mutant Notch3 protein that leads to the manifestation of the CADASIL syndrome in order to spot possible conserved mutations and interpret the effect of these mutations in the Notch3 protein structure. Conserved mutations of cysteine residues may be candidate pharmacological targets for the potential therapy of CADASIL syndrome.

Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-β plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3β, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.