ABSTRACT
@#Studies suggest that synaptic damage is closely associated with cognitive dysfunction, and lemur tyrosine kinase 1 (LMTK1) is a key kinase that affects synaptic growth. Dihydroergotamine (DHE) is an ergot alkaloid derivative with high biological activity, which could regulate cognition, memory processing and motor control.This study aims to investigate the effect of DHE on synapse atrophy and plasticity as well as cognition in Alzheimer’s disease (AD) model animals.SAMR1 mice were selected as control group (n = 12).SAMP8 mice were randomly divided into 3 groups (n = 12 for each group):AD group, DHE low-dose group and high-dose group.The DHE groups were injected DHE intraperitoneally daily for 8 weeks.Immunofluorescence experiments, Golgi staining experiment, electrophysiological experiment, Morris water maze experiment (MWM) and Western blot experiment were conducted to investigate the effect of DHE on synaptic morphology, synaptic plasticity, cognitive function as well as the phosphorylation level of LMTK1 downstream TBC1D9B in AD model mice.Subsequently, the LMTK1 silencing and overexpression cells were constructed.Immunofluorescence experiments were used to study the effect of DHE on synaptic length of nerve cell after LMTK1 silencing and overexpression.In the hippocampus of AD mice, the postsynaptic marker PSD95 was significantly increased after DHE administration, which suggested that DHE could increase the synaptic density. In Golgi staining experiment, synaptic atrophy was observed in the hippocampal of AD mice, which could be improved by high-dose DHE.Compared with normal mice, the long-term potentiation (LTP) level of AD model mice was significantly reduced (P < 0.000 1), DHE could increase LTP significantly.The MWM experiment further showed that DHE could improve cognitive function in AD mice.WB experiments showed that the level of P-LMTK1 in the hippocampus of AD mice increased significantly, and the level of downstream P-TBC1D9B decreased significantly after DHE administration.Cell immunofluorescence experiments in vitro had shown that DHE significantly improved synaptic atrophy in overexpressed C17.2 cells, while its improvement disappeared when LMTK1 was silenced. This research suggests DHE may improve synaptic atrophy and cognitive dysfunction in AD by targeting on LMTK1.
ABSTRACT
Abstract@#Alzheimer's disease (AD) is a neurodegenerative disease characterized by deposition of β-amyloid (Aβ). Liver X receptors (LXRs), a member of the nuclear receptor transcription factor superfamily, are widely expressed in brain, which may be involved in the development and progression of AD. Based on the international and national publications pertaining to the association between LXRs and AD from 2010 to 2022, this review summarizes the advances on the involvement of LXRs in the regulation of cholesterol metabolism, inflammatory response and synapse formation in the pathogenesis of AD was reviewed, so as to provide insights into the prevention and treatment of AD.
ABSTRACT
ObjectiveTo investigate the mechanism of Dihuang Yinzi in improving astrocyte injury and protecting synaptic structure and function in the brain of Alzheimer's disease （AD） mice. MethodForty male APP/PS1 transgenic mice aged four months were randomly divided into a model group and a model + Dihuang Yinzi （0.25 g·kg-1） group， with 20 mice in each group. Forty C57BL/6J mice with the same background and same age were randomly divided into a control group and a control + Dihuang Yinzi （0.25 g·kg-1） group， with 20 mice in each group. The mice in the control + Dihuang Yinzi group and the model + Dihuang Yinzi group were administered with Dihuang Yinzi by gavage， and those in the control group and the model group received an equal volume of sterilized normal saline， once a day for 150 days. The learning and memory ability of mice was tested by the light-dark box test and Y-maze spontaneous alternation test. The content of glutamate （Glu） and glutamine （Gln） was measured by liquid chromatography-tandem mass spectrometry （LC-MS）. Long-term potentiation （LTP） assay was used to detect synaptic plasticity in brain tissues. The protein expression levels of excitatory amino acid transporter 2 （EAAT2）， postsynaptic density protein95 （PSD95）， and synaptophysin （SYN） in brain tissues were measured by Western blot. Immunofluorescence was used to assess the localization and expression of EAAT2. Colorimetry was performed to detect Na+-K+ ATPase activity in mouse brain tissues. ResultAs compared with the control group， the model group showed shortened residence latency （P<0.01）， increased number of errors （P<0.01） in the light-dark box test， reduced spontaneous alternation behaviors （P<0.01）， no significant difference in the total number of arm entries in the Y-maze spontaneous alternation test， down-regulated expression of EAAT2， PSD95， and SYN （P<0.01）， blunted activity of Na+-K+ ATPase （P<0.01）， up-regulated Glu level （P<0.01）， down-regulated Gln level （P<0.01）， and reduced relative population spike （PS） amplitude and the slope of excitatory postsynaptic potential （EPSP） （P<0.05， P<0.01）， while the above experimental indexes were not significantly different in the control + Dihuang Yinzi group. Compared with the model group， the model + Dihuang Yinzi group displayed prolonged residence latency （P<0.05）， decreased number of errors （P<0.01） in the light-dark box test， increased spontaneous alternation behaviors （P<0.01）， no significant difference in the total number of arm entries in the Y-maze spontaneous alternation test， up-regulated expression of EAAT2， PSD95， and SYN （P<0.01）， potentiated activity of Na+-K+ ATPase （P<0.01）， reduced Glu level （P<0.01）， up-regulated Gln level （P<0.01）， and increased PS amplitude and EPSP slope （P<0.01）. ConclusionDihuang Yinzi can improve cognitive dysfunction in AD mice by protecting astrocytes， increasing Glu uptake to reduce its abnormal accumulation， and protecting synaptic structure and function.
ABSTRACT
The bionic optic nerve can mimic human visual physiology and is a future treatment for visual disorders. Photosynaptic devices could respond to light stimuli and mimic normal optic nerve function. By modifying (Poly(3,4-ethylenedioxythio-phene):poly (styrenesulfonate)) active layers with all-inorganic perovskite quantum dots, with an aqueous solution as the dielectric layer in this paper, we developed a photosynaptic device based on an organic electrochemical transistor (OECT). The optical switching response time of OECT was 3.7 s. To improve the optical response of the device, a 365 nm, 300 mW·cm -2 UV light source was used. Basic synaptic behaviors such as postsynaptic currents (0.225 mA) at a light pulse duration of 4 s and double pulse facilitation at a light pulse duration of 1 s and pulse interval of 1 s were simulated. By changing the way light stimulates, for example, by adjusting the intensity of the light pulses from 180 to 540 mW·cm -2, the duration from 1 to 20 s, and the number of light pulses from 1 to 20, the postsynaptic currents were increased by 0.350 mA, 0.420 mA, and 0.466 mA, respectively. As such, we realized the effective shift from short-term synaptic plasticity (100 s recovery of initial value) to long-term synaptic plasticity (84.3% of 250 s decay maximum). This optical synapse has a high potential for simulating the human optic nerve.
Subject(s)
Humans , Quantum Dots , Bionics , Oxides , Optic NerveABSTRACT
Background Neurotransmitter secretion disorder induced by chronic manganese poisoning has always been one of the important causes of body injury, but the mechanism of neurotransmitter secretion disorder caused by manganese is not clear at present. Objective To investigate the effects of presynaptic membrane intracellular protein 13-1 (Munc13-1) and synapse fusion protein binding protein 18-1 (Munc18-1) on dopamine secretion dysfunction induced by manganese chloride (MnCl2) in human neuroblastoma (SH-SY5Y) cells. Methods A SH-SY5Y cell model induced by MnCl2 was established. Cell viability was measured by MTT assay. Four experimental groups were set up: control group and low-, medium-, and high-dose manganese groups (0, 100, 200, and 400 μmol·L−1 MnCl2). They were treated with corresponding doses of MnCl2 for 24 h. The secretion of dopamine was measured by enzyme-linked immunosorbent assay. The mRNA expression of Syntaxin-1 was detected by real-time quantitaive PCR. Total cell proteins were extracted, and the protein expression levels of Munc13-1, Munc18-1, and Syntaxin-1 were detected by Western blotting. The correlations of MnCl2 exposure and dopamine secretion with the protein expressions of Munc13-1 and Munc18-1 were also analyzed by Pearson correlation. Results Compared with the control group, the cell viability rate decreased gradually with the increase of manganese exposure concentration, and the difference between the medium- and the high-dose manganese groups was statistically significant (P<0.05). The concentration of dopamine in cell culture medium of all manganese exposure groups decreased with the increase of manganese concentration, and compared with the control group and the low-dose manganese group, the medium- and the high-dose manganese groups were statistically significant (P<0.05). The expression of Syntaxin-1 at mRNA or protein level did not change significantly among groups (P>0.05). Compared with the control group, the protein expression of Munc13-1 decreased and that of Munc18-1 increased with the increase of manganese concentration (P<0.05). Compared with the low-dose manganese group, the changes of Munc13-1 protein in the high-dose manganese group and Munc18-1 protein in the medium- and high-dose manganese groups had statistical significance (P<0.05). Compared with the medium-dose manganese group, the protein changes of Munc18-1 in the high-dose manganese group were statistically significant (P<0.05). The correlation analysis showed that MnCl2 dose was negatively correlated with Munc13-1 protein expression (r=−0.898, P<0.05), and positively correlated with Munc18-1 protein expression (r=0.678, P<0.05). Dopamine secretion was positively correlated with Munc13-1 protein expression (r=0.932, P<0.05), and negatively correlated with Munc18-1 protein expression (r=−0.817, P<0.05). Conclusion The inhibition of dopamine secretion in SH-SY5Y cells induced by manganese exposure is related to up-regulation of Munc18-1 and down-regulation of Munc13-1 expression levels, which may be one of the reasons for nerve injury caused by manganese.
ABSTRACT
ObjectiveTo construct a neural network-like tissue with the potential of synaptic formation in vitro by seeding human induced pluripotent stem cell-derived neural precursor cells （hiPSC-NPCs） on decellularized optic nerve （DON）， so as to provide a promising approach for repair of nerve tissue injury. MethodsThrough directional induction and tissue engineering technology， human induced pluripotent stem cells （hiPSCs） and 3D DON scaffolds were combined to construct neural network-like tissues. Then the hiPSCs were directionally induced into human neural precursor cells （hNPCs） and neurons. Immunofluorescence staining was used to identify cell differentiation efficiency. 3D DON scaffolds were prepared. Morphology and cytocompatibility of scaffolds were identified by scanning electron microscopy and Tunnel staining. Induced hiPSC-NPCs were seeded on DON scaffolds. Immunofluorescence staining， scanning electron microscopy， transmission electron microscopy and patch clamp were used to observe the morphology and functional identification of constructed neural network tissues. Results①The results of immunofluorescence staining suggested that most of hiPSC-NPCs differentiated into neurons in vitro. We had successfully constructed a neural network dominated by neurons. ② The results of scanning electron microscopy and immunohistochemistry suggested that a neural network-like tissue with predominating excitatory neurons in vitro was successfully constructed. ③The results of immunohistochemical staining， transmission electron microscopy and patch clamp indicated that the neural network-like tissue had synaptic transmission function. ConclusionA neural network-like tissue mainly composed of excitatory neurons has been constructed by the combination of natural uniform-channel DON scaffold and hiPSC-NPCs， which has the function of synaptic transmission. This neural network plays a significant role in stem cell derived replacement therapy， and offers a promising prospect for repair of spinal cord injury （SCI） and other neural tissue injuries.
ABSTRACT
OBJECTIVE To study the effects of Dianxianqing granules on the tau protein in P301S mice by regulating mitophagy. METHODS Totally 36 P301S mice were randomly divided into model group， Dianxianqing granule group （12.48 g/kg）， donepezil hydrochloride group （positive control， 1.3 mg/kg）， with 12 mice in each group； another 10 C57BL6 mice were selected as control group. Administration groups were given relevant drug solutions intragastrically， and control group and model group were given constant volume of water intragastrically. The gavage volume was 20 mL/kg， once a day， for consecutive 5 months. During the experiment， the general condition of mice was observed in each group. After the last medication， the learning and memory ability was determined by Y maze test and Morris water maze test； HE staining was used to observe the morphological changes in brain tissue， and Nissl staining was used to observe the structure of neural cells and the number of Nissl bodies in cerebral tissue. Immunohistochemistry was used to detect the expressions of phospho-tau serine 202/threonine 205 （abbreviated as AT8） in brain tissue. Western blot assay was used to determine the expressions of mitophagy-associated proteins [PTEN-induced putative kinase-1 （PINK1）， Parkin， microtubule-associated protein 1 light chain 3B （LC3B）， p62]， synaptic-associated proteins [postsynaptic density protein-95 （PSD-95）， synaptophysin （SYP）， and growth-associated protein-43 （GAP-43）] and the phosphorylation of tau protein [expressed by the phosphorylation levels of serine 199 （Ser199） and Ser202] in brain tissue. RESULTS The mice in E-mail：lnzyxyqy2003@163.com model group showed symptoms such as white hair， decreased body mass， and lower limb paralysis， with incomplete hippocampal structures in their brain tissue， as well as incomplete cell membrane edges and cell structures； the spontaneous alternating response rate， the times of crossing platform， the number of Nissl bodies， the protein expressions of PINK1， Parkin， LC3B， SYP， GAP-43， and PSD-95 were decreased significantly， compared with control group； swimming latency （fourth and fifth day）， the protein expressions of AT8 and p62，the phosphorylation levels of Ser199 and Ser202 were increased or lengthened significantly， compared with control group （P＜0.05 or P＜0.01）. Compared with model group， the above symptoms and indexes of mice were improved significantly in administration groups （P＜0.05 or P＜0.01）. CONCLUSIONS Dianxianqing granules can effectively improve cognitive impairment in P301S mice，the mechanism of which may be associated with inducing mitochondrial autophagy， reducing the hyperphosphorylation of tau protein， up-regulating the expression of synaptic-associated proteins in brain tissue，and repairing damaged neural cells.
ABSTRACT
Human brain cholesterol acts as structural components of cellular membrane, synapse and dendrite formation.Researchers have found a possible association between low serum cholesterol levels and mood disorders though the literature from India in this regard is limited. To estimate serum levels of total cholesterol in patients with major depressive disorder. 75 patients of MDD were compared with equal number of age and sex matched controls. 5 ml of fasting sample of blood was obtained in a plain vacutainer to analyse total cholesterol level by Cholesterol oxidase-peroxidase method. Statistical analysis: The obtained results were tabulated and analyzed by multiple logistic regression analysis, independent t-test, Chi-square test and area under the curve. The mean level of cholesterol in cases (158.85±61.22 mg/dL) which was significantly lower compared to the controls (182.71±40.98 mg/dL) with P <0.01. The symptoms of MDD negatively correlated with lower serum cholesterol level with odds ratio of 0.99. There was statistically significant lower level of cholesterol in the MDD group below 140 mg/dL compared to the control group with P <0.001. As the measurement of total serum cholesterol is simple and cost effective, it can be used as an important biochemical marker for MDD.
ABSTRACT
This paper aim is to discuss and clarify about the way we perceived the functionality of the synapse since 4th century BC up to modern times and actual status. The discussions over the way synapses work began over 2400 years ago and it all started from the simple question of how the locomotive system works and how do the muscles contract. The rst who discussed about this concept was Plato during the 4th century BC. We are discussing about René Descartes (1596-1650) depiction of a clear view in the book entitled “De Homine” (1662) over the view of the brain and the innervation of the body. In modern times, the word “synapse” was coined for the rst time in Michael Foster's 7th Edition “Textbook of Physiology” of 1897 , for which Sherrington wrote 3 chapters. He proposed his former Professor to introduce the word “synapse” which comes from Greek and means “conjunction”. For this discovery, Charles Sherrington and Edgar Douglas Adrian were awarded the Nobel Prize in Physiology or Medicine in 1932.
ABSTRACT
Objective:To explore the effect of enriched environment on pain sensitivity, anxiety- and depressive-like behavior in selective nerve injury(SNI) rats model and its potential mechanism.Methods:A total of 36 male clean grade SD rats aged 6-8 weeks were randomly divided into three groups( n=12 in each group): sham operation+ standard environment group (sham group), SNI+ standard environment group (standard environment group), SNI+ enriched environment group (enriched environment group). The rat model of neuropathic pain was established by SNI.The rats in the enriched enviroment group were placed in an enriched enviroment 7 days before operation until 21 days after operation.The paw withdraw threshold(PWT) and paw withdraw latency (PWL) were performed to assess hyperalgesia.The open field test, elevated plus maze test, novelty suppressed feeding test and forced swimming test were used to assess anxiety and depression like behavior.The expressions of cAMP response element binding protein (CREB), p-CREB, brain-derived neurotrophic factor (BDNF), postsynaptic density-95 (PSD-95) and neuroligin 2 (NLGN2) were detected by Western blot.The expression of CREB and BDNF in contralateral ACC were measured by immunofluorescence.GraphPad prism 8.0 and SPSS 23.0 were used for data analysis.One way ANOVA was used for inter group comparison, repeated measurement ANOVA was used to analyze PWT and PWL results, and Tukey test was used for pairwise comparison. Results:(1) In PWT and PWL experiments, the interaction effect between group and time, group main effect and time main effect of PWT were significant ( F=13.4, 39.6, 369.6, all P<0.05), and the interaction effect between group and time, group main effect and time main effect of PWL were significant ( F=3.8, 10.3, 58.8, all P<0.05). Compared with sham group, PWT((8.0±3.5) g, (2.4±1.4) g, (2.3±1.1) g, (2.2±1.6) g, (1.6±0.5) g) and PWL((8.6±1.3) s, (7.3±1.5) s, (7.9±1.0) s, (6.6±1.1) s, (7.7±1.4) s) in standard environment group decreased at each time point (all P<0.05). (2) Compared with sham group, the number of entrying into the central area (1.3±1.7), the time of entrying into the central area((1.6±1.3) s), the proportion of entering open arms ((8.0±7.8) %) and the proportion of time in the open arms ((1.3±1.2) %) all significantly decreased in standard environment group ( t=4.585, 5.423, 4.682, 5.202, all P<0.05). The eating latency ((365.2±94.4) s) and immobility time ((127.6±24.3) s) dramatically increased ( t=6.008, 14.290, both P<0.05). The number and time of entrying into central area of enriched environment group were both higher than those of standard environment group(both P<0.05), while the eating latency and immobility time of enriched environment group were both lower than those of standard environment group(both P<0.05). (3) Compared with sham group(CREB: (1.6±0.2), (0.8±0.5); BDNF: (0.8±0.5), (1.0±0.4)), the expression of CREB ((1.8±0.1), (1.5±0.2)), BDNF ((0.9±0.6), (1.4±0.3)) in spinal cord and ACC of standard environment group increased (spinal: t=3.283, 4.989; ACC: t=5.502, 4.257, all P<0.05). The expression of PSD-95 ((1.6±0.2), (1.0±0.2) and NLGN2 ((1.5±0.5), (1.1±0.2)) also increased in ACC of standard enviroment group ( t=4.257, 2.214, both P<0.05). Compared with standard environment group, the expression of CREB (1.3±0.3), BDNF (0.7±0.4), PSD-95(1.0±0.3) and NLGN2(1.1±0.4) in spinal cord of enriched environment group decreased ( t=5.007, 2.166, 2.358, 2.322, all P<0.05). The expression of PSD-95(1.2±0.3) and NLGN2(1.1±0.2) also decreased in ACC of enriched environment group ( t=2.674, 2.944, both P<0.05). However, the expression of p-CREB (1.7±0.6) and BDNF (2.4±0.2) increased in ACC ( t=4.180, 7.610, P<0.05). Conclusion:Enriched environment can improve neuropathic pain and anxiety- and depressive-like behavior in SNI rats, which may be related to the change of synaptic plasticity in spinal cord and ACC.
ABSTRACT
During the development of visual cortex, the structure of neurons will adaptively change and adjust according to the changes of external environment, which shows structural plasticity.The experience-dependent plasticity of visual cortex is based on the structural changes of neurons, which mainly include change of synaptic connections, disappearance or increase of dendritic spines, turnover of dendritic spines, changes in the size of dendritic spines, changes in postsynaptic density and alterations of perineuronal nets.The structural changes of neurons have significant influence on the plasticity of visual cortex function and structure, and are highly associated with some molecules or non-neuronal components such as paired immunoglobulin-like receptor B, Ly-6/neurotoxin-like protein 1, Nogo, microglia and extracellular matrix and so on.In addition, external intervention factors such as abnormal visual experience and environmental enrichment can have significant impact on the regulation of the structural changes of neurons, and finally influence the development of visual function and the recovery from visual impairment.In comparison with the functional studies, studies on the structural plasticity of visual cortical neurons depend on the state-of-the-art imaging techniques at cellular or sub-cellular level with more visualizable and convincing results.The constant exploration of the structural plasticity of visual cortex will enhance our understanding of visual development-related diseases, such as amblyopia, and lay the foundation for related basic research and innovative treatments.Advances in the structural plasticity of visual cortex were reviewed in this article.
ABSTRACT
ObjectiveTo observe the effect of Wenyang Jieyu decoction （WYJY） on the hippocampal structure of depressed rats with kidney-yang deficiency. MethodThe 105 SD rats were randomly divided into normal group， model group， fluoxetine group （4.17 mg·kg-1）， Xiaoyaosan group （1.88 g·kg-1）， and low-， medium- and high-dose （1.25，2.50，5.00 g·kg-1） WYJY groups，15 in each group. The depression model was induced by subcutaneous injection of corticosterone in rats except for those in the normal group and the rats were orally administered once a day for 28 days. The depression-like behaviors of rats were observed by sucrose preference test， novelty-suppressed feeding test， forced swimming test， and open field test. The morphology of hippocampal neurons was observed by hematoxylin-eosin（HE） staining， and the density of hippocampal neurons was detected by Nissl staining. The ultrastructure of hippocampal synapses was observed by transmission electron microscopy （TEM）. The expression of synaptophysin （SYP）， postsynaptic density-95 （PSD95）， and apoptosis-related protein Caspase-3 in hippocampal neurons was observed by immunohistochemistry， and bromodeoxyuridine （BrdU） and doublecortin （DCX） were used to observe the apoptosis and regeneration of hippocampal neurons. ResultWYJY could improve weight loss in depressed rats. As revealed by the behavioral tests， the model group showed depression-like behaviors， which were relieved in the WYJY groups and the positive drug groups. HE staining showed that the nuclei of hippocampal neurons in the model group were constricted， deeply stained， and sparsely arranged， while the neurons in the WYJY groups and the positive drug groups were significantly improved. Nissl staining demonstrated that the cell density of the model group was lower than that of the normal group （P<0.05）. Compared with model group， the groups with drug intervention showed increased cell density （P<0.05） and compact arrangement. According to the results in TEM， compared with normal group， the model group showed shortened synaptic active zone （P<0.05）， widened synaptic cleft （P<0.05）， and thinned tight zone （P<0.05）. Compared with model group， the groups with drug intervention showed shortened synaptic active zone （P<0.05）， narrowed synaptic cleft （P<0.05）， and thickened tight zone （P<0.05）. As displayed by the results of immunocytochemistry and immunofluorescence， compared with the normal group， the model group showed decreased protein expression of SYP， PSD95， BrdU， and DCX in the hippocampus （P<0.05） and increased protein expression of Caspase-3 （P<0.05）. Compared with the model group， the groups with drug intervention showed increased protein expression of SYP， PSD95， BrdU， and DCX in the hippocampus （P<0.05） and decreased protein expression of Caspase-3 （P<0.05）. ConclusionWYJY can promote the regeneration of hippocampal neurons in rats and improve the depression of rats.
ABSTRACT
Recent studies have revealed great functional and structural heterogeneity in the ribbon-type synapses at the basolateral pole of the isopotential inner hair cell (IHC). This feature is believed to be critical for audition over a wide dynamic range, but whether the spatial gradient of ribbon morphology is fine-tuned in each IHC and how the mitochondrial network is organized to meet local energy demands of synaptic transmission remain unclear. By means of three-dimensional electron microscopy and artificial intelligence-based algorithms, we demonstrated the cell-wide structural quantification of ribbons and mitochondria in mature mid-cochlear IHCs of mice. We found that adjacent IHCs in staggered pairs differ substantially in cell body shape and ribbon morphology gradient as well as mitochondrial organization. Moreover, our analysis argues for a location-specific arrangement of correlated ribbon and mitochondrial function at the basolateral IHC pole.
Subject(s)
Animals , Mice , Artificial Intelligence , Cochlea/metabolism , Hair Cells, Auditory, Inner , Mitochondria , Synapses/metabolismABSTRACT
Myoclonus dystonia syndrome (MDS) is an inherited movement disorder, and most MDS-related mutations have so far been found in the ε-sarcoglycan (SGCE) coding gene. By generating SGCE-knockout (KO) and human 237 C > T mutation knock-in (KI) mice, we showed here that both KO and KI mice exerted typical movement defects similar to those of MDS patients. SGCE promoted filopodia development in vitro and inhibited excitatory synapse formation both in vivo and in vitro. Loss of function of SGCE leading to excessive excitatory synapses that may ultimately contribute to MDS pathology. Indeed, using a zebrafish MDS model, we found that among 1700 screened chemical compounds, Vigabatrin was the most potent in readily reversing MDS symptoms of mouse disease models. Our study strengthens the notion that mutations of SGCE lead to MDS and most likely, SGCE functions to brake synaptogenesis in the CNS.
ABSTRACT
Objective:To investigate the effect of electroacupuncture (EA) on synaptic damage to hippocampal neurons in rats with sepsis-associated encephalopathy (SAE).Methods:A total of 48 healthy adult male Sprague-Dawley rats, weighing 250-300 g, were divided into 4 groups ( n=12 each) using a random number table method: sham operation group (Sham group), SAE group, SAE+ EA group and SAE+ sham EA group (SAE+ SEA group). SAE was induced by cecal ligation and puncture in anesthetized rats.Baihui, Quchi and Zusanli acupoints were stimulated with constant voltage (2/15 Hz) and disperse-dense waves for 30 min once a day for 10 consecutive days, and the stimulation intensity was defined as less than 1.5 mA causing slight muscle contraction at 2 days before operation in group SAE+ EA.In group SAE+ SEA, stimulating electrodes were placed at the points 5 mm lateral to the corresponding acupoints, but no electrical stimulation was applied.On day 14 after operation, the rats were sacrificed, and hippocampal tissues were obtained and stained with haematoxylin and eosin for examination of the pathological changes in the hippocampal CA1 region, for determination of the expression of synaptophysin (SYN) and postsynaptic density protein 95 (PSD-95) (by Western blot), and for calculation of dendritic spine density of neurons in the hippocampal CA1 area (using Golgi staining) and pyramidal neurons counts. Results:Compared with Sham group, the expression of SYN and PSD-95 in hippocampus was significantly decreased, and the basal and apical dendrite spine density of neurons in hippocampal CA1 area was decreased in SAE group, the expression of PSD-95 was decreased, and the apical dendrite spine density of neurons in the hippocampal CA1 area was increased in SAE+ EA group, and the pyramidal neuron counts in the hippocampal CA1 area were reduced in SAE, SAE+ EA and SAE+ SEA groups ( P<0.05). Compared with group SAE, the expression of SYN and PSD-95 was significantly up-regulated, the basal and apical dendrite spine density of neurons in the hippocampal CA1 area was increased and the pyramidal neuron counts were increased in group SAE+ EA ( P<0.05), the pathological damage of hippocampal CA1 area was alleviated and no significant change was found in the parameters mentioned above in group SAE+ SEA ( P>0.05). Compared with group SAE+ EA, the expression of SYN and PSD-95 was down-regulated, the basal and apical dendrite spine density of neurons in the hippocampal CA1 area was decreased, and the pyramidal neuron counts were reduced in SAE+ SEA group ( P<0.05). Conclusion:The mechanism by which EA alleviates SAE may be related to reducing synaptic damage to hippocampal neurons in rats.
ABSTRACT
Objective:To observe the expression levels of glial fibrillary acidic protein (GFAP), β-tubulin Ⅲ and synaptophsin, and explore the role of tripartite synapse in the mechanism of central nervous system (CNS) injury and the neuroprotective effect of chondroitin sulfate (CS).Methods:One month old clean grade, 48 female Sparague-Dawley rats and 48 male Sparague-Dawley rats, were randomly divided into 8 groups according to body weight (90 - 120 g) by random number table method, with 12 rats in each group, half male and half female. These rats were fed with water containing different concentrations of sodium fluoride (NaF) [ < 0.5 mg/L (control, CN), 10.0 mg/L (low dose fluoride, LF) and 50.0 mg/L (high dose fluoride, HF)]. Some rats were fed directly for 185 days (CN, LF and HF groups). In addition, rats of CN + normal saline (NS), LF + NS, HF + NS groups and LF + CS, HF + CS groups, were intraperitoneally injected with NS or 0.66 mg/kg CS for 5 consecutive days after 180 days of feeding. After the experiment, the pathological changes of hippocampal CA4 of brain tissue in each group were observed by hematoxylin eosin staining under light microscope, and the expression and distribution of GFAP, β-tubulin Ⅲ and synaptophsin in hippocampal CA4 of rats were detected by immunohistochemistry, the expression of GFAP, β-tubulin Ⅲ and synaptophsin at protein level in hippocampus of rats were detected by Western blotting.Results:Under light microscope, eosinophilic change, loss and irregular arrangement of neuron in the hippocampal CA4 were observed in LF, HF, LF + NS and HF + NS groups. The morphology of LF + CS and HF + CS groups was not significantly changed compared with CN group, but was significant changed compared with LF, HF, LF + NS and HF + NS groups. Immunohistochemical results showed that the rates of positive area of GFAP, β-tubulin Ⅲ and synaptophsin in female and male rats in LF and HF groups were significantly decreased than those in CN group ( P < 0.05); the positive area rates of female and male rats in LF + CS and HF + CS groups were higher than those in LF and HF groups, respectively ( P < 0.05). Western blotting results showed that the proten expression levels of GFAP, β-tubulin Ⅲ and synaptophsin of female and male rats in LF and HF groups (LF group: 0.90 ± 0.09, 0.82 ± 0.08, 1.43 ± 0.14, 0.92 ± 0.02, 1.21 ± 0.15, 0.87 ± 0.02, HF group: 0.58 ± 0.14, 0.73 ± 0.03, 0.63 ± 0.06, 0.67 ± 0.03, 0.87 ± 0.04, 0.70 ± 0.05) were lower than those in CN group (1.24 ± 0.08, 1.09 ± 0.10, 2.64 ± 0.30, 1.54 ± 0.09, 1.72 ± 0.10, 1.13 ± 0.06, P < 0.05). Conclusions:The tripartite synapse and extracellular matrix may take part in pathogenesis of the damages of CNS results from chronic fluorosis; CS may reduce the injury to a certain extent.
ABSTRACT
Objective:To explore the therapeutic effect and mechanism of Chaihu Yueju decoction on model rats induced by chronic unpredictable mild stress （CUMS）. Method:The 60 SD rats were randomly divided into normal group， model group， Chaihu Yueju decoction low， medium and high-dose groups（0.3， 0.6， 1.2 g·kg-1） and fluoxetine hydrochloride group（0.2 mg·kg-1）， 10 for each group. The model rats was established by chronic unpredictable mild stress for 5 weeks， and then Chaihu Yueju decoction and fluoxetine hydrochloride were given to the corresponding treatment group by gavage for 3 weeks. In the last week of gavage， Morris water maze training and testing were conducted. After the last day of gavage， sugar water preference and other behavioral experiment were tested. The sugar water preference test was used to detect the degree of pleasure deficiency in rats before and after treatment， the open field test was used to detect the depression of rats before and after treatment， the spatial memory ability was tested by Morris water maze. Western blot was used to detect the levels of tumor necrosis factor-α（TNF-α）， 5-hydroxytryptamine receptor 1A （5-HT1A）， extracellular signal-regulated kinase （ERK） and synapse associated protein in hippocampus of each group， Gloji and Nissl staining was used to observe the changes of dendritic spines and Nissl bodies in the hippocampus CA3. Result:Compared with normal group， the weight， sugar water preference rate， the scores of horizontal and vertical movement were significantly reduced （P<0.05）， and the immobility time was significantly prolonged in model group （P<0.05）. Meanwhile， the ability of learning and memory in model group decreased （P<0.05）. Western blot results showed that the levels of TNF-α was significantly increased （P<0.05）， and the levels of 5-HT1A， p-ERK， cyclic adenosine phosphate reactive element binding protein （CREB）， p-CREB， Synapsin-1，Synaptophysin， glutamate receptor subtype-1（GluR-1）and postsynaptic membrane protein-95（PSD-95） in model group were significantly decreased （P<0.05）. Gloji and Nissl staining results showed that the density of dendritic spines and the number of Nissl body in the hippocampal CA3 of the model group was obviously attenuate （P<0.05）. The results show that the neurons were evidently damaged. Compared with model group， the weight， sugar water preference rate， the scores of horizontal and vertical movement were clearly increased （P<0.05） and the immobility time was significantly shortened in fluoxetine hydrochloride group， middle dose and high dose Chaihu Yueju decoction group （P<0.05）. Western blot results showed that the levels of synaptophysin， GluR-1 and PSD-95 were significantly increased in fluoxetine hydrochloride group， middle dose and high dose Chaihu Yueju decoction group. The level of TNF-α was significantly decreased （P<0.05）， the levels of 5-HT1A， p-ERK， CREB， p-CREB and Synapsin-1 were remarkably increased （P<0.05）， especially the high dose group of Chaihu Yueju decoction. Gloji and Nissl staining results showed that the density of dendritic spines and the number of Nissl body in the hippocampal CA3 of high dose group were similarly increased in a dose-dependent manner. Conclusion:Chaihu Yueju decoction could improves the weight， the depressive despair， autonomous activity ability and learning and memory ability of DP model rats. Its mechanism is closely related to attenuating the inflammatory reaction and enhancing the levels of 5-HT1A receptor protein， ERK and synapse related protein， then activating 5-HT/CREB and ERK/CREB signaling pathways， increasing the number and distribution of dendritic spines and repairing damaged neurons in the DP model rat's hippocampus.
ABSTRACT
Neuroligin is a key protein that mediates synaptic development and maturation, and is closely related to neurodevelopmental diseases such as autism. In recent years, researchers have found that neuroligin can be hydrolyzed by various proteases at different stages of development, neuronal activities or pathological states of some neuropsychiatric diseases, thus affecting synaptic activity and participating in the occurrence and development of neurological diseases. The hydrolysates may have different physiological functions from the whole protein, and play different functions in neural activities, such as regulating synaptic plasticity, increasing synaptic strength and number, affecting amyloid-β polymerization, promoting glioma proliferation and growth, activating related signaling pathways, and so on. In this article, on the basis of elaborating the structure and function of neuroligin as a whole protein, the conditions and products of its hydrolysis are summarized and analyzed, and the functional consequences and physiological significance of its hydrolysis are discussed.
ABSTRACT
Objective: To investigate the mechanism of depression by Sini Powder. Methods: The chemical composition and targets of Bupleuri Radix, Paeonia Radix Alba, Aurantii Fructus Immaturus, and Glycyrrhizae Radix et Rhizoma were searched by the analysis of traditional Chinese medicine system pharmacology platform (TCMSP). Depression related genes were screened from OMIM, TDD, Drugbank, and Digsee multiple databases. The target corresponding genes were searched through UniProt, GeneCards, and PubMed database query and then Cytoscape 3.2.1 was used to build compound-targets (genes) networks, protein interaction (PPI) filter core targe; At last, the enrichment of gene ontology (GO) function analysis by DAVID based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was carried out, and the mechanism of its action research was predicted. Results: The compound-target network contained 121 compounds and the corresponding 259 targets, and the key targets involved PTGS2, CALM1, ESR1, HSP90AA1, AR, etc. The PPI core network contained 15 proteins, key proteins involved in CASP3, CHRM2, CYP3A4, and etc. The function enrichment analysis of GO was 375 (P < 0.05), of which there were 307 biological processes (BP), and 37 related items of cell composition (CC), and 31 molecular function (MF) items. 37 related items of cell composition (CC), and 31 molecular function (MF) items. There were 37 signal pathways (P < 0.05) in KEGG pathway enrichment screening, involving neuroactive ligand-receptor interaction, dopaminergic synapse, IL-17 signaling pathway and so on. Conclusion: The active components in Sini Powder play an antidepressant role by acting on 15 key targets such as CASP3, CHRM2, DRD1 to regulate multiple signaling pathways.
ABSTRACT
Neuroligins (NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal model studies, and affect synaptic connections and synaptic plasticity in several brain regions. Yet current research mainly focuses on pyramidal neurons, while the function of NLs in interneurons remains to be understood. To explore the functional difference among NLs in the subtype-specific synapse formation of both pyramidal neurons and interneurons, we performed viral-mediated shRNA knockdown of NLs in cultured rat cortical neurons and examined the synapses in the two major types of neurons. Our results showed that in both types of neurons, NL1 and NL3 were involved in excitatory synapse formation, and NL2 in GABAergic synapse formation. Interestingly, NL1 affected GABAergic synapse formation more specifically than NL3, and NL2 affected excitatory synapse density preferentially in pyramidal neurons. In summary, our results demonstrated that different NLs play distinct roles in regulating the development and balance of excitatory and inhibitory synapses in pyramidal neurons and interneurons.