SYP Expression Research Articles

The role of Imp and Syp RNA-binding proteins in precise neuronal elimination by apoptosis through the regulation of transcription factors.

Neuronal stem cells generate a limited and consistent number of neuronal progenies, each possessing distinct morphologies and functions, which are crucial for optimal brain function. Our study focused on a neuroblast (NB) lineage in Drosophila known as Lin A/15, which generates motoneurons (MNs) and glia. Intriguingly, Lin A/15 NB dedicates 40% of its time to producing immature MNs (iMNs) that are subsequently eliminated through apoptosis. Two RNA-binding proteins, Imp and Syp, play crucial roles in this process. Imp+ MNs survive, while Imp-, Syp+ MNs undergo apoptosis. Genetic experiments show that Imp promotes survival, whereas Syp promotes cell death in iMNs. Late-born MNs, which fail to express a functional code of transcription factors (mTFs) that control their morphological fate, are subject to elimination. Manipulating the expression of Imp and Syp in Lin A/15 NB and progeny leads to a shift of TF code in late-born MNs toward that of early-born MNs, and their survival. Additionally, introducing the TF code of early-born MNs into late-born MNs also promoted their survival. These findings demonstrate that the differential expression of Imp and Syp in iMNs links precise neuronal generation and distinct identities through the regulation of mTFs. Both Imp and Syp are conserved in vertebrates, suggesting that they play a fundamental role in precise neurogenesis across species.

Prenatal diesel exhaust exposure alters hippocampal synaptic plasticity in offspring.

Diesel exhaust particles (DEPs) are major air pollutants emitted from automobile engines. Prenatal exposure to DEPs has been linked to neurodevelopmental and neurodegenerative diseases associated with aging. However, the specific mechanism by DEPs impair the hippocampal synaptic plasticity in the offspring remains unclear. Pregnant C57BL/6 mice were administered DEPs solution via the tail vein every other day for a total of 10 injections, then the male offsprings were studied to assess learning and memory by the Morris water maze. Additionally, protein expression in the hippocampus, including CPEB3, NMDAR (NR1, NR2A, NR2B), PKA, SYP, PSD95, and p-CREB was analyzed using Western blotting and immunohistochemistry. The alterations in the histomorphology of the hippocampus were observed in male offspring on postnatal day 7 following prenatal exposure to DEPs. Furthermore, 8-week-old male offspring exposed to DEPs during prenatal development exhibited impairments in the Morris water maze test, indicating deficits in learning and memory. Mechanistically, the findings from our study indicate that exposure to DEPs during pregnancy may alter the expression of CPEB3, SYP, PSD95, NMDAR (NR1, NR2A, and NR2B), PKA, and p-CREB in the hippocampus of both immature and mature male offspring. The results offer evidence for the role of the NMDAR/PKA/CREB and CPEB3 signaling pathway in mediating the learning and memory toxicity of DEPs in male offspring mice. The alterations in signaling pathways may contribute to the observed damage to synaptic structure and transmission function plasticity caused by DEPs. The findings hold potential for informing future safety assessments of DEPs.

Qingzhuan dark tea Theabrownin alleviates hippocampal injury in HFD-induced obese mice through the MARK4/NLRP3 pathway

BackgroundFeeding on a high-fat diet (HFD) results in obesity and chronic inflammation, which may have long-term effects on neuroinflammation and hippocampal injury. Theabrownin, a biologically active compound derived from the microbial fermentation of Qingzhuan dark tea, exhibits anti-inflammatory properties and lipid-lowering effects. Nevertheless, its potential in neuroprotection has yet to be investigated. Consequently, this study aims to investigate the neuroprotective effects of Theabrownin extracted from Qingzhuan dark tea, as well as its potential therapeutic mechanisms. MethodsMale C57 mice were subjected to an 8-week HFD to induce obesity, followed by oral administration of Theabrownin from Qingzhuan dark tea. Lipid levels were detected by Elisa kit, hippocampal morphological damage was evaluated by HE and Nissl staining, and the expression levels of GFAP, IBA1, NLRP3, MARK4, and BAX in the hippocampus were detected by immunofluorescence (IF), and protein expression levels of NLRP3, MARK4, PSD95, SYN1, SYP, and Bcl-2 were detected by Western Blot (WB). ResultsTheabrownin treatment from Qingzhuan dark tea prevents alterations in body weight and lipid levels in HFD-fed mice. Furthermore, Theabrownin decreased hippocampal morphological damage and reduced the activation of astrocytes and microglia in HFD-fed mice. Moreover, Theabrownin decreased the expression of MARK4 and NLRP3 in HFD-fed mice. Besides, Theabrownin elevated the expression of PSD95, SYN1, and SYP in HFD-fed obese mice. Finally, Theabrownin prevented neuronal apoptosis, reduced the expression of BAX, and increased the expression of Bcl-2 in HFD-fed obese mice. ConclusionsIn summary, our current study presents the first demonstration of the effective protective effect of Theabrownin from Qingzhuan dark tea against HFD-induced hippocampal damage in obese mice. This protection may result from the regulation of the MARK4/NLRP3 signaling pathway, subsequently inhibiting neuroinflammation, synaptic plasticity, and neuronal apoptosis.

Radix Bupleuri aqueous extract attenuates MK801-induced schizophrenia-like symptoms in mice: Participation of intestinal flora

Schizophrenia (SCZ) is a psychotic mental disorder characterized by cognitive, behavioral, and social impairments. However, current pharmacological treatment regimens are subpar in terms of effectiveness. This study aimed to investigate the function of Radix Bupleuri aqueous extract in SCZ in mouse models. The SCZ mouse model was established by MK-801 injection and feeding of Radix Bupleuri aqueous extract or combined antibiotics. Radix Bupleuri aqueous extract significantly improved the aberrant behaviors and neuronal damage in SCZ mice, upregulated SYP and PSD-95 expression and BDNF levels in hippocampal homogenates, down-regulated DA and 5-HT levels, and suppressed microglial activation in SCZ mice. Moreover, Radix Bupleuri aqueous extract improved the integrity of the intestinal tract barrier. The 16 S rRNA sequencing of feces showed that Radix Bupleuri extract modulated the composition of gut flora. Lactobacillus abundance was decreased in SCZ mice and reversed by Radix Bupleuri aqueous extract administration which exhibited a significant negative correlation with IL-6, IL-1β, DA, and 5-HT, and a significant positive correlation with BDNF levels in hippocampal tissues. The abundance of Parabacteroides and Alloprevotella was increased in SCZ mice. It was reversed by Radix Bupleuri aqueous extract administration, which exhibited a positive correlation with IL-6, IL-1β, and 5-HT and a negative correlation with BDNF. In conclusion, Radix Bupleuri aqueous extract attenuates the inflammatory response in hippocampal tissues and modulates neurotransmitter levels, exerting its neuroprotective effect in SCZ. Meanwhile, the alteration of intestinal flora may be involved in this process, which is expected to be an underlying therapeutic option in treating SCZ.

OR01-05 Growth Hormone Action In Somatostatin Neurons Regulates Anxiety And Fear Memory

Abstract Disclosure: W.O. dos Santos: None. V.A. Juliano: None. H.R. Vieira: None. R. Frazao: None. C.D. Munhoz: None. J. Donato: None. Dysfunctions in growth hormone (GH) secretion increase the prevalence of anxiety and depression. Furthermore, GH receptor (GHR) signaling in the amygdala has been associated with fear memory, a key feature of post-traumatic stress disorder. However, it is currently unknown which neuronal population is targeted by GH action to influence neuropsychiatric diseases. Here we showed that approximately 60% of somatostatin (SST)-expressing neurons in the extended amygdala are directly responsive to GH. GHR ablation in SST-expressing cells (SSTΔGHR mice) led to increased anxiety in the light-dark box and elevated plus maze tests, whereas SSTΔGHR females showed no changes in anxiety, compared to control animals. Using auditory Pavlovian fear conditioning, both male and female SSTΔGHR mice exhibited a significant reduction in fear memory. In contrast, GHR ablation in SST neurons did not affect memory in the novel object recognition test. The gene expression was analyzed in a bilateral micropunch comprising the central nucleus of the amygdala and basolateral complex of male mice. Increased mRNA expression of Gabbr2 (GABAB2 receptor), Syp (synaptophysin), and Bdnf were observed in the amygdala of SSTΔGHR mice. In conclusion, GHR expression in SST neurons is necessary to regulate anxiety in males, but not in female mice. GHR ablation in SST neurons also decreases fear memory and affects the gene expression in the amygdala. Our findings identified for the first time a specific neuronal population responsible for mediating the effects of GH on behavioral aspects associated with neuropsychiatric diseases. Presentation: Thursday, June 15, 2023

SAT605 Growth Hormone Action In Somatostatin Neurons Regulates Anxiety And Fear Memory

Abstract Disclosure: W.O. dos Santos: None. V.A. Juliano: None. H.R. Vieira: None. R. Frazao: None. C.D. Munhoz: None. J. Donato: None. Dysfunctions in growth hormone (GH) secretion increase the prevalence of anxiety and depression. Furthermore, GH receptor (GHR) signaling in the amygdala has been associated with fear memory, a key feature of post-traumatic stress disorder. However, it is currently unknown which neuronal population is targeted by GH action to influence neuropsychiatric diseases. Here we showed that approximately 60% of somatostatin (SST)-expressing neurons in the extended amygdala are directly responsive to GH. GHR ablation in SST-expressing cells (SSTΔGHR mice) led to increased anxiety in the light-dark box and elevated plus maze tests, whereas SSTΔGHR females showed no changes in anxiety, compared to control animals. Using auditory Pavlovian fear conditioning, both male and female SSTΔGHR mice exhibited a significant reduction in fear memory. In contrast, GHR ablation in SST neurons did not affect memory in the novel object recognition test. The gene expression was analyzed in a bilateral micropunch comprising the central nucleus of the amygdala and basolateral complex of male mice. Increased mRNA expression of Gabbr2 (GABAB2 receptor), Syp (synaptophysin), and Bdnf were observed in the amygdala of SSTΔGHR mice. In conclusion, GHR expression in SST neurons is necessary to regulate anxiety in males, but not in female mice. GHR ablation in SST neurons also decreases fear memory and affects the gene expression in the amygdala. Our findings identified for the first time a specific neuronal population responsible for mediating the effects of GH on behavioral aspects associated with neuropsychiatric diseases. Presentation: Saturday, June 17, 2023

Integrating Network Pharmacology and Component Analysis to Study the Potential Mechanisms of Qi-Fu-Yin Decoction in Treating Alzheimer's Disease.

To elucidate the potential mechanisms of QFY for the treatment of Alzheimer's Disease (AD), and explore the effective substances of QFY. UPLC-LTQ-Orbitrap-MS was used to identify the chemical constituents of the serum samples and the cerebrospinal fluid samples of rats after QFY administration. Network pharmacology was used to predict potential targets and pathways of QFY against AD. The AD mice model was established by subcutaneous injection of D-gal for 8 consecutive weeks. New object recognition (NOR) and Morris water maze test (MWM) were used to evaluate the learning and memory abilities of mice. Moreover, the levels of TNF-α, IL-1β, and IL-18 in the brain hippocampus of mice were determined by ELISA. The expression of Bax, Bcl-2, Caspase-1, PSD95, SYP, ICAM-1 and MCP-1 proteins in the hippocampus was detected by Western blotting. Furthermore, qRT-PCR was used to detect the gene expressions of PSD95, SYP, M1 and M2 polarization markers of microglia, including iNOS, CD16, ARG-1, and IL-10 in the hippocampus. A total of 51 prototype compounds were detected in rat serum and 15 prototype components were identified in rat cerebrospinal fluid. Behavioral experiments revealed that QFY significantly increased the recognition index, decreased the escape latency, increased the platform crossing times and increased the residence time in the target quadrant. QFY also could alleviate the ultrastructural pathological changes in the hippocampus of AD mice. Meanwhile, QFY treatment suppressed the expression of inflammatory factors, such as TNF-α, IL-1β, and IL-18. QFY improved the synaptic plasticity of the hippocampus in D-gal model mice by significantly increasing the expression of proteins and mRNAs of PSD95 and SYP. QFY could effectively improve the learning and memory impairment of D-gal-induced AD mice by inhibiting the excessive activation of microglia, enhancing the expression of M2 microglia, inhibiting the increase of inflammatory factors, cell adhesion factors and chemokines, anti-apoptosis, and improving synaptic plasticity.

VPA-induced autism impairs memory ability through disturbing neural oscillatory patterns in offspring rats.

Autism spectrum disorder (ASD) is a general neurodevelopmental disease characterized by unusual social communication and rigid, repetitive behavior patterns. The purpose of this study was to investigate the effects of ASD on the alteration of neural oscillatory patterns and synaptic plasticity, which commonly supported a wide range of basic and higher memory activities. Accordingly, a prenatal valproic acid (VPA) exposure rat model was established for studying autism. The behavioral experiments showed that the social orientation declined and the memory ability was significantly impaired in VPA rats, which was closely associated with the synaptic plasticity deficits. Neural oscillation is the rhythmic neuron-activity, and the pathological characteristics and neurological changes in autism may be peeped at the neural oscillatory analysis. Interestingly, neural oscillatory analysis showed that prenatal VPA exposure reduced the low-frequency power but increased high-frequency gamma (HG) power in the hippocampus CA1 area. Meanwhile, the coherence and synchronization between CA3 and CA1 were abnormally increased in the VPA group, especially in theta and HG rhythms. Furthermore, the cross-frequency coupling strength of theta-LG in the CA1 and CA3 → CA1 pathway was significantly attenuated, but the theta-HG coupling strength was increased. Additionally, prenatal VPA exposure inhibited the expression of SYP and NR2B but enhanced the expression of PSD-95 along with decreased synaptic plasticity. The neural oscillatory patterns in VPA-induced offspring were disturbed with the intensity and direction of neural information flow disordered, which are consistent with the changes in synaptic plasticity, suggesting that the decline in synaptic plasticity is the underlying mechanism.

ZIP9 mediates the effects of DHT on learning, memory and hippocampal synaptic plasticity of male Tfm and APP/PS1 mice.

Androgens are closely associated with functions of hippocampal learning, memory, and synaptic plasticity. The zinc transporter ZIP9 (SLC39A9) regulates androgen effects as a binding site distinct from the androgen receptor (AR). However, it is still unclear whether androgens regulate their functions in hippocampus of mice through ZIP9. Compared with wild-type (WT) male mice, we found that AR-deficient male testicular feminization mutation (Tfm) mice with low androgen levels had learning and memory impairment, decreased expression of hippocampal synaptic proteins PSD95, drebrin, SYP, and dendritic spine density. Dihydrotestosterone (DHT) supplementation significantly improved these conditions in Tfm male mice, although the beneficial effects disappeared after hippocampal ZIP9 knockdown. To explore the underlying mechanism, we first detected the phosphorylation of ERK1/2 and eIF4E in the hippocampus and found that it was lower in Tfm male mice than in WT male mice, it upregulated with DHT supplementation, and it downregulated after hippocampal ZIP9 knockdown. Next, we found that the expression of PSD95, p-ERK1/2, and p-eIF4E increased in DHT-treated mouse hippocampal neuron HT22 cells, and ZIP9 knockdown or overexpression inhibited or further enhanced these effects. Using the ERK1/2 specific inhibitor SCH772984 and eIF4E specific inhibitor eFT508, we found that DHT activated ERK1/2 through ZIP9, resulting in eIF4E phosphorylation, thus promoting PSD95 protein expression in HT22 cells. Finally, we found that ZIP9 mediated the effects of DHT on the expression of synaptic proteins PSD95, drebrin, SYP, and dendritic spine density in the hippocampus of APP/PS1 mice through the ERK1/2-eIF4E pathway and affected learning and memory. This study demonstrated that androgen affected learning and memory in mice through ZIP9, providing new experimental evidence for improvement in learning and memory in Alzheimer's disease with androgen supplementation.

Activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in a chronic migraine rat model

BackgroundCentral sensitization has been widely accepted as an underlying pathophysiological mechanism of chronic migraine (CM), activation of cannabinoid type-1 receptor (CB1R) exerts antinociceptive effects by relieving central sensitization in many pain models. However, the role of CB1R in the central sensitization of CM is still unclear.MethodsA CM model was established by infusing inflammatory soup (IS) into the dura of male Wistar rats for 7 days, and hyperalgesia was assessed by the mechanical and thermal thresholds. In the periaqueductal gray (PAG), the mRNA and protein levels of CB1R and hyperpolarization-activated cyclic nucleotide-gated cation channel 2 (HCN2) were measured by qRT–PCR and western blotting. After intraventricular injection of Noladin ether (NE) (a CB1R agonist), ZD 7288 (an HCN2 blocker), and AM 251 (a CB1R antagonist), the expression of tyrosine phosphorylation of N-methyl-D-aspartate receptor subtype 2B (pNR2B), calcium-calmodulin-dependent kinase II (CaMKII), and phosphorylated cAMP-responsive element binding protein (pCREB) was detected, and central sensitization was evaluated by the expression of calcitonin gene-related peptide (CGRP), c-Fos, and substance P (SP). Synaptic-associated protein (postsynaptic density protein 95 (PSD95) and synaptophysin (Syp)) and synaptic ultrastructure were detected to explore synaptic plasticity in central sensitization.ResultsWe observed that the mRNA and protein levels of CB1R and HCN2 were both significantly increased in the PAG of CM rats. The application of NE or ZD 7288 ameliorated IS-induced hyperalgesia; repressed the pNR2B/CaMKII/pCREB pathway; reduced CGRP, c-Fos, SP, PSD95, and Syp expression; and inhibited synaptic transmission. Strikingly, the application of ZD 7288 relieved AM 251-evoked elevation of pNR2B, CGRP, and c-Fos expression.ConclusionsThese data reveal that activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in CM rats. The activation of CB1R might have a positive influence on the prevention of CM by mitigating central sensitization.

Quantitative proteomics analysis in small cell carcinoma of cervix reveals novel therapeutic targets

BackgroundAs a rare pathologic subtype, small cell carcinoma of the cervix (SCCC) is characterized by extensive aggressiveness and resistance to current therapies. To date, our knowledge of SCCC origin and progression is limited and sometimes even controversial. Herein, we explored the whole-protein expression profiles in a panel of SCCC cases, aiming to provide more evidence for the precise diagnosis and targeting therapy.MethodsEighteen SCCC samples and six matched normal cervix tissues were collected from January 2013 to December 2017. Data independent acquisition mass spectrometry (DIA) was performed to discriminate the different proteins (DEPs) associated with SCCC. The expression of CDN2A and SYP in corresponding SCCC tissues was verified using immunohistochemistry. GO and KEGG enrichment analyses were used to identify the key DEPs related to SCCC development and tumor recurrence.ResultsAs a result, 1311 DEPs were identified in SCCC tissues (780 up-regulated and 531 down-regulated). In up-regulated DEPs, both GO analysis and KEGG analysis showed the most enriched were related to DNA replication (including nuclear DNA replication, DNA-dependent DNA replication, and cell cycle DNA replication), indicating the prosperous proliferation in SCCC. As for the down-regulated DEPs, GO analysis showed that the most enriched functions were associated with extracellular matrix collagen-containing extracellular matrix. KEGG analysis revealed that the DEPs were enriched in Complement and coagulation cascades, proteoglycans in cancer, and focal adhesion-related pathways. Down-regulation of these proteins could enhance the mobility of cancer cells and establish a favorable microenvironment for tumor metastasis, which might be accounted for the frequent local and distant metastasis in SCCC. Surprisingly, the blood vessels and circulatory system exhibit a down-regulation in SCCC, which might be partly responsible for its resistance to anti-angiogenic regimens. In the stratification analysis of early-stage tumors, a group of enzymes involved in the cancer metabolism was discriminated in these recurrence cases.ConclusionsUsing quantitative proteomics analysis, we first reported the whole-protein expression profiles in SCCC. Significant alterations were found in proteins associated with the enhancement of DNA replication and cellular motility. Besides the association with mitosis, a unique metabolic feature was detected in cases with tumor recurrence. These findings provided novel targets for disease surveillance and treatments, which warranted further validation in the future.

Copper Induces Cognitive Impairment in Mice via Modulation of Cuproptosis and CREB Signaling

It has been reported that disordered Cu metabolism is associated with several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the underlying mechanism is still unclear. In this study, 4-week-old male mice were exposed to Cu by free-drinking water for three months. Then, the effects of Cu on cognitive functions in mice were tested by Morris water maze tests, and the potential mechanisms were investigated by the ELISA, immunochemistry, TUNEL, and Western blot tests. It was found that Cu exacerbates learning and memory impairment, and leads to Cu-overload in the brain and urine of mice. The results showed that Cu induces neuronal degeneration and oxidative damage, promotes the expression of apoptosis-related protein Bax, cuproptosis-related proteins FDX1 and DLAT and the proteotoxic stress marker HSP70, and decreases Fe-S cluster proteins. In addition, Cu affects the pre-synaptic and post-synaptic regulatory mechanisms through inhibiting the expression of PSD-95 and SYP. Cu also suppresses phosphorylation levels in CREB and decreases the expression of BDNF and TrkB in the mouse hippocampus. In conclusion, Cu might mediate cuproptosis, damage synaptic plasticity and inhibit the CREB/BDNF pathway to cause cognitive dysfunction in mice.

Exploring the mechanism of Chaihujia Longgu Muli decoction in the treatment of epilepsy in rats based on the RhoA/ROCK signaling pathway.

The Chinese herbal formula Chaihujia Longgu Muli Decoction (CD) has a good antiepileptic effect, but its mechanisms remain unclear. Therefore, in this study we explored the molecular mechanisms of CD against epilepsy. Twelve-day-old SD rats were randomly divided into a normal group, model group, valproic acid group, and CD high, medium, and low groups. Except for the normal group, the other groups were given an intraperitoneal injection of pentylenetetrazol (PTZ) to establish epilepsy models, and the Racine score was applied for model judgment. After 14 consecutive days of dosing, the Morris water maze test was performed. Then, hippocampal Nissl staining and immunofluorescence staining were performed, and synaptic ultrastructure was observed by transmission electron microscopy (TEM). RhoA/ROCK signaling pathway proteins were detected. In PTZ model rats, the passing times were reduced, and the escape latency was prolonged in the Morris water maze test. Nissl staining showed that some hippocampal neurons swelled and ruptured, Nissl bodies in the cytoplasm were significantly reduced, and neurons were lost. Immunofluorescence detection revealed that the expression of PSD95 and SYP was significantly reduced. Electron microscopy results revealed that the number of synapses in hippocampal neurons was significantly reduced and the postsynaptic membrane length was significantly reduced. Western blot analysis showed that the RhoA/ROCK signaling pathway was activated, while SYP, SPD95, and PTEN expression was significantly decreased. After treatment with CD, neurobehavioral abnormalities and neuronal damage caused by epileptic seizures were improved. CD exerted an antiepileptic effect by inhibiting the activation of the RhoA/ROCK signaling pathway.

DNA hypomethylation promotes learning and memory recovery in a rat model of cerebral ischemia/reperfusion injury.

Cerebral ischemia/reperfusion injury impairs learning and memory in patients. Studies have shown that synaptic function is involved in the formation and development of memory, and that DNA methylation plays a key role in the regulation of learning and memory. To investigate the role of DNA hypomethylation in cerebral ischemia/reperfusion injury, in this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery and then treated the rats with intraperitoneal 5-aza-2'-deoxycytidine, an inhibitor of DNA methylation. Our results showed that 5-aza-2'-deoxycytidine markedly improved the neurological function, and cognitive, social and spatial memory abilities, and dose-dependently increased the synaptic density and the expression of SYP and SHANK2 proteins in the hippocampus in a dose-dependent manner in rats with cerebral ischemia/reperfusion injury. The effects of 5-aza-2'-deoxycytidine were closely related to its reduction of genomic DNA methylation and DNA methylation at specific sites of the Syp and Shank2 genes in rats with cerebral ischemia/reperfusion injury. These findings suggest that inhibition of DNA methylation by 5-aza-2'-deoxycytidine promotes the recovery of learning and memory impairment in a rat model of cerebral ischemia/reperfusion injury. These results provide theoretical evidence for stroke treatment using epigenetic methods.

Effect of induced diabetes on morphometric indexes of the cerebellar cortex and gene expression in C57BL mice.

Diabetes is a metabolic disorder that affects the development of the central nervous system and plays an important role in learning and memory. Diabetes increases the reactive oxygen species (ROS) level in cells and changes the expression of several genes, including SYP, BDNF, PAX7, and SYNCAM1, through the FOXO transcription factor. This study was done to assess the effect of diabetes on morphometric indexes of the cerebellar cortex and gene expression in mice. Diabetes was induced in twelve adult, male C57BL mice using an injection of streptozotocin. After two months, the mice were dissected, and the cerebellum was stored for further analysis. For the morphometric analysis, tissue sections were stained with cresyl violet and examined with a light microscope. For gene expression analysis, the RNA was extracted, and cDNA was synthesized. The mRNA levels of SYP, BDNF, PAX7, and SYNCAM1 genes were measured by the real-time PCR method. The thickness of the molecular layer and Purkinje layer, and the number of Purkinje and granular cells in the diabetic group were significantly reduced compared to controls P<0.0 1). The area, perimeter, and diameter of Purkinje cells in the diabetic group were significantly reduced compared to controls P<0.0 1). The expression of PAX7, SYP, and BDNF genes of the diabetic group was significantly reduced. However, SYNCAM1 expression in the cerebellum of the diabetic group was significantly increased compared to controls (P<0.05). Induced diabetes in mice can decrease the expression of memory-related genes in the cerebellum. Also, these genes affect the morphology and thickness of the cerebellum.

Circ-Vps41 positively modulates Syp and its overexpression improves memory ability in aging mice.

Age is an established risk factor for neurodegenerative disorders. Aging-related cognitive decline is a common cause of memory impairment in aging individuals, in which hippocampal synaptic plasticity and hippocampus-dependent memory formation are damaged. Circular RNAs (circRNAs) have been reported in many cognitive disorders, but their role in aging-related memory impairment is unclear.Methods: In this study, we aimed to investigate the effects of circ-Vps41 on aging-related hippocampus-dependent memory impairment and explore the potential mechanisms. Here, D-galactose was used to produce a conventional aging model resulting in memory dysfunction. Circ-Vps41 was significantly downregulated in D-galactose-induced aging in vitro and in vivo. The overexpression of circ-Vps41 could upregulate synaptophysin (Syp), thereby promoting the synaptic plasticity and alleviating cognitive impairment in aging mice. Mechanistically, we found that circ-Vps41 upregulated Syp expression by physically binding to miR-24-3p. Moreover, the miR-24-3p mimics reversed the circ-Vps41 overexpression-induced increase in Syp expression. Overexpression of circ-Vps41 alleviated the synaptic plasticity and memory dysfunction via the miR-24-3p/Syp axis. These findings revealed circ-Vps41 regulatory network and provided new insights into its potential mechanisms for improving aging-related learning and memory impairment.

The protective role of hippocampal LRP1 knockdown involves synaptic plasticity through the promoting microtubule dynamics and activation of Akt/GSK-3β pathway in depressive rats

BackgroundThe mechanism by which synaptic plasticity mediates the occurrence of depression is unknown. Low-density lipoprotein receptor-related protein 1 (LRP1) affects axon growth and neurogenesis in the brain, but its role in depressive-like behaviors is poorly understood. MethodsAdeno-associated virus-mediated small interfering RNA was injected into the bilateral hippocampus 14 days before chronic unpredicted mild stress (CUMS). Behavior performance was assessed for depressive-like behaviors. Western blot was conducted to detect levels of LRP1, neurogenesis-related proteins, synaptic markers, microtubule system molecules and Akt/GSK-3β signaling-related proteins. Immunohistochemical staining was performed for LRP1 protein, immunofluorescence staining was conducted to determine the Sox2 protein, Nissl's staining and transmission electron microscope staining were used to observe hippocampal morphological features. ResultsThe expression of hippocampal LRP1 was positively correlated with depressive-like behaviors. Treatment with iAAV-LRP1 exerted protective effects on depressive-like behaviors. LRP1 Knockdown relieved the inhibition of synaptic plasticity induced by CUMS. Expression of Sox2, GluR2 and SYP was significantly increased in iAAV-LRP1 CUMS rats. LRP1 knockdown reduced the p-tau (Ser262 and Thr404) and Acet-tubule levels in depressed rats. Finally, we found that LRP1 knockdown activated the PI3K/Akt pathway and inhibited GSK-3β signal transduction. LimitationsMore neurogenesis markers would be considered, and stereotactic injection into hippocampal DG region could be performed to investigate the effects of LRP1. ConclusionsThese findings indicated that hippocampal LRP1 deficiency in stressed rats plays an important protective role in depressive-like behavior by increasing synaptic plasticity mediated by microtubule dynamic and activating Akt/GSK-3β signaling pathway. Therefore, LRP1 may represent a potential therapeutic target for depression.

Prenatal benzo[a]pyrene exposure impairs hippocampal synaptic plasticity and cognitive function in SD rat offspring during adolescence and adulthood via HDAC2-mediated histone deacetylation

Benzo[a]pyrene (B[a]P) is a widespread carcinogenic pollutant in the environment. Although previous studies have demonstrated the neurodevelopmental toxicity of B[a]P, the precise mechanisms underlying the neurotoxic effects induced by prenatal B[a]P exposure remain largely unknown. In the present study, pregnant Sprague-Dawley (SD) rats were injected intraperitoneally with 0, 10, 20, or 40 mg/kg-bw of B[a]P for three consecutive days on embryonic days 17–19. The learning and memory abilities of offspring were determined by Morris Water Maze (MWM) test, while the number of dendritic branches and the density of dendritic spines in hippocampal CA1 and DG regions were evaluated by Golgi-Cox staining at PND 45 and PND 75. The mRNA expression of BDNF, PSD-95, and SYP in offspring hippocampus were detected by qRT-PCR, and the protein expression of BDNF, PSD-95, SYP, HDAC2, acH3K9, and acH3K14 were measured by Western blotting or immunohistochemistry. CHIP-PCR was performed to further detect the levels of acH3K9 and acH3K14 in the promoter regions of BDNF and PSD-95 genes. Our results showed that rats prenatally exposed to B[a]P exhibited impaired spatial learning and memory abilities and the number of dendritic branches and the density of dendritic spines in the hippocampal CA1 and DG regions were significantly reduced during adolescence and adulthood. The expression of HDAC2 protein was significantly upregulated, while acH3K9, acH3K14, BDNF, PSD-95, and SYP protein levels were significantly downregulated in the hippocampus of B[a]P- exposed rats. In addition, CHIP results showed that prenatal B[a]P exposure markedly decreased the level of acH3K9 and acH3K14 in the promoter region of BDNF and PSD-95 gene in the hippocampus of PND 45 and PND 75 offspring. All of the results suggest that prenatal B[a]P exposure impairs cognitive function and hippocampal synaptic plasticity of offspring in adolescence and adulthood, and HDAC2-mediated histone deacetylation plays a crucial role in these deficits.

Cognitive dysfunctions and spontaneous EEG alterations induced by hippocampal amyloid pathology in rats

PurposeWe aimed to determine the effects of different doses of amyloid-beta (Aβ) peptide on learning and memory, and whether the changes in brain oscillations induced by dose-dependent accumulation of Aβ could be used as biomarkers to detect early stages of Alzheimer's disease (AD). Material and methodsMale albino Wistar rats aged 3 months were randomly divided into four groups (n ​= ​12/group) obtained by i. h. Injection (to the dorsal hippocampus) of saline or different doses of 0.01 ​μg/μl, 0.1 ​μg/μl, and 1 ​μg/μl of Aβ. After two weeks of recovery period, open field and novel object recognition tests were performed and spontaneous EEG recordings were obtained. Later, hippocampus tissues were collected for Western blot and ELISA analysis. ResultsA significant decrement in recognition memory was observed in 0.1 ​μg/μl, and 1 ​μg/μl injected groups. In addition, Aβ accumulation induced significant decrement of the expression of NeuN, SNAP-25, SYP, and PSD-95 proteins, and led to the increment of GFAP expression in hippocampus. Moreover, we detected remarkable alterations in spontaneous brain activity. The hippocampal Aβ levels were negatively correlated with hippocampal gamma power and positively correlated with hippocampal theta power. Also, we observed significant changes in coherence values, indicating the functional connectivity between different brain regions, after the accumulation of Aβ. Especially, there was a significant correlation between changes in frontohippocampal theta coherence and in frontotemporal theta coherence. ConclusionsOur findings indicate that Aβ peptide induces AD-like molecular changes at certain doses, and these changes could be detected by evaluating brain oscillations.

Brain structure and synaptic protein expression alterations after antidepressant treatment in a Wistar–Kyoto rat model of depression

BackgroundStructural MRI has demonstrated brain alterations in depression pathology and antidepressants treatment. While synaptic plasticity has been previously proposed as the potential underlying mechanism of MRI findings at a cellular and molecular scale, there is still insufficient evidence to link the MRI findings and synaptic plasticity mechanisms in depression pathology. MethodsIn this study, a Wistar-Kyoto (WKY) depression rat model was treated with antidepressants (citalopram or Jie-Yu Pills) and tested in a series of behavioral tests and a 7.0 MRI scanner. We then measured dendritic spine density within altered brain regions. We also examined expression of synaptic marker proteins (PSD-95 and SYP). ResultsWKY rats exhibited depression-like behaviors in the sucrose preference test (SPT) and forced swim test (FST), and anxiety-like behaviors in the open field test (OFT). Both antidepressants reversed behavioral changes in SPT and OFT but not in FST. We found a correlation between SPT performance and brain volumes as detected by MRI. All structural changes were consistent with alterations of the corpus callosum (white matter), dendritic spine density, as well as PSD95 and SYP expression at different levels. Two antidepressants similarly reversed these macro- and micro-changes. LimitationsThe single dose of antidepressants was the major limitation of this study. Further studies should focus on the white matter microstructure changes and myelin-related protein alterations, in addition to comparing the effects of ketamine. ConclusionTranslational evidence links structural MRI changes and synaptic plasticity alterations, which promote our understanding of SPT mechanisms and antidepressant response in WKY rats.