Thickness Of Postsynaptic Density Research Articles

Systematic review and Meta-analysis of brain plasticity associated with electroacupuncture in experimental ischemic stroke.

To systematically evaluate the role of electroacupuncture in maintaining brain plasticity in ischemic stroke mediated brain damage. We searched for all relevant trials published through Oct 7, 2022 from seven databases. Metho-dological quality was assessed using the CAMARADES Risk of Bias Tool. A Meta-analysis of comparative effects was performed using Review Manager v.5.3 software. A total of 101 studies involving 2148 animals were included. For most studies, primary outcomes results of the Meta-analysis indicate that EA significantly improved ischemic stroke rat's postsynaptic density thickness [Standardized Mean Difference (SMD) = 1.41, 95% confidence interval (CI) (0.59, 2.23), P = 0.0008], numerical density of synapses [SMD = 1.55, 95% CI (0.48, 2.63), P = 0.005] compared with non-EA-treated. Similarly, EA could improve parts of biomarkers of synapses, neurogenesis, angiogenesis and neurotrophin activity than the control group (P < 0.05). The existing evidence suggests EA regulating ischemic stroke may be through brain plasticity. More rigorous and high quality studies should be conducted in the future.

High-frequency rTMS alleviates cognitive impairment and regulates synaptic plasticity in the hippocampus of rats with cerebral ischemia

Poststroke cognitive impairment (PSCI) is a common complication of stroke, but effective treatments are currently lacking. Repetitive transcranial magnetic stimulation (rTMS) is gradually being applied to treat PSCI, but there is limited evidence of its efficacy. To determine rTMS effects on PSCI, we constructed a transient middle cerebral artery occlusion (tMCAO) rat model. Rats were then grouped by random digital table method: the sham group (n = 10), tMCAO group (n = 10) and rTMS group (n = 10). The shuttle box and Morris water maze (MWM) tests were conducted to detect the cognitive functions of the rats. In addition, synaptic density and synaptic ultrastructural parameters, including the active zone length, synaptic cleft width, and postsynaptic density (PSD) thickness, were quantified and analyzed using an electron microscope. What’s more, synaptic associated proteins, including PSD95, SYN, and BDNF were detected by western blot. According to the shuttle box and MWM tests, rTMS improved tMCAO rats’ cognitive functions, including spatial learning and memory and decision-making abilities. Electron microscopy revealed that rTMS significantly increased the synaptic density, synaptic active zone length and PSD thickness and decreased the synaptic cleft width. The western blot results showed that the expression of PSD95, SYN, and BDNF was markedly increased after rTMS stimulation. Based on these results, we propose that 20 Hz rTMS can significantly alleviate cognitive impairment after stroke. The underlying mechanism might be modulating the synaptic plasticity and up-regulating the expression PSD95, SYN, and BDNF in the hippocampus.

The effect of acupuncture on hippocampal synaptic plasticity in Alzheimer Disease Mouse Model: Possible mechanisms of energy transportation in neurons

Objective: To study the mechanism of acupuncture-promoted synaptic plasticity in hippocampal neurons of senescence-accelerated mouse-prone 8 mice with respect to neuronal energy substrate transport. Methods: Forty-three senescence-accelerated mouse-prone 8 mice were randomly divided into Alzheimer’s disease model and acupuncture groups, and twenty senescence-accelerated mouse resistant 1 mice were used as the normal group. Acupuncture group received acupuncture at the “Baihui” and “Yongquan” acupoints for 40 days. The Morris water maze was used to detect the learning and memory capabilities of the mice, and in vivo electrophysiology and transmission electron microscopy were used to evaluate the synaptic functional and structural plasticity of hippocampal neurons. Glucose, lactate, and pyruvate in the hippocampal intercellular fluid, as well as the expression of glucose transporter 3 and monocarboxylate transporters 2 and 4, were analyzed using microdialysis, immunohistochemistry, and western blotting. Results: The Morris water maze data showed that compared with Alzheimer’s disease model mice, mice of acupuncture group exhibited a shorter escape latency, increased number of effective zone crossings, and increased percentage of swimming distance in the target quadrant. Acupuncture increased the postsynaptic density thickness of Alzheimer’s disease model mice and decreased the latency amplitude after tetanic stimulation and width of the synaptic cleft. Glucose, lactate, and pyruvate contents in the hippocampal intercellular fluid were significantly reduced in Alzheimer’s disease model mice, but the reductions were more pronounced after acupuncture treatment. Furthermore, acupuncture prominently elevated glucose transporter 3 and monocarboxylate transporters 2 expression in the CA1 and dentate gyrus regions of the hippocampus of Alzheimer’s disease model mice. The elevation of monocarboxylate transporters 4 expression mostly appeared in the CA1 region. Conclusion: Acupuncture improved the learning and memory capabilities as well as the hippocampal synaptic structural plasticity of senescence-accelerated mouse-prone 8 mice. Its effects were likely related to the regulation of glucose transporter 3, monocarboxylate transporters 2, and monocarboxylate transporters 4 expression in the hippocampal tissue to increase the energy substrate reserve of neurons and improve the substrate-matching ability of the cellular response.

Alcohol Consumption During Adolescence Alters the Cognitive Function in Adult Male Mice by Persistently Increasing Levels of DUSP6.

Binge alcohol drinking during adolescence has long-term effects on the adult brain that alter brain structure and behaviors, but the underlying mechanisms remain poorly understood. Extracellular signal-regulated kinase (ERK) is involved in the synaptic plasticity and pathological brain injury by regulating the expression of cyclic adenosine monophosphate response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF). Dual-specificity phosphatase 6 (DUSP6) is a critical effector that dephosphorylates ERK1/2 to control the basal tone, amplitude, and duration of ERK signaling. To explore DUSP6 as a regulator of ERK signaling in the mPFC and its impact on long-term effects of alcohol, a male mouse model of adolescent intermittent alcohol (AIA) exposure was established. Behavioral experiments showed that AIA did not affect anxiety-like behavior or sociability in adulthood, but significantly damaged new object recognition and social recognition memory. Molecular studies further found that AIA reduced the levels of pERK-pCREB-BDNF-PSD95/NR2A involved in synaptic plasticity, while DUSP6 was significantly increased. Intra-mPFC infusion of AAV-DUSP6-shRNA restored the dendritic spine density and postsynaptic density thickness by reversing the level of p-ERK and its downstream molecular expression, and ultimately repaired adult cognitive impairment caused by chronic alcohol exposure during adolescence. These findings indicate that AIA exposure inhibits ERK-CREB-BDNF-PSD95/NR2A by increasing DUSP6 in the mPFC in adulthood that may be associated with long-lasting cognitive deficits.

Hydrogen sulfide attenuates depression-like behaviours in Parkinson's disease model rats by improving synaptic plasticity in a hippocampal Warburg effect-dependent manner

BackgroundDepression is a highly prevalent comorbidity arising in patients with Parkinson's disease (PD). However, depression in patients with PD is poorly treated. Hydrogen sulfide (H2S), a neuromodulator, has the potential to relieve depression. ObjectiveTo investigate whether H2S attenuates depression-like behaviours in a rat model of PD and examine the underlying mechanisms. MethodsWe utilised rotenone to develop a PD model with subcutaneous injections in the dorsal cervical region of Sprague-Dawley rats. The depression-like behaviours in the rotenone-induced PD model rats were assessed through forced swimming, tail suspension, open field, novelty-suppressed feeding, and elevated plus-maze tests. The expression of postsynaptic density protein-95 and synapsin-1, related to synaptic plasticity, was detected using Western blot in the hippocampus. The hippocampal ultrastructure, including the synaptic density, length of the synaptic active zone, postsynaptic density thickness, and synaptic gap width, was detected using transmission electron microscopy. ResultsWe proved that sodium hydrosulfide (NaHS; a donor of H2S) significantly attenuated the depression-like behaviours and disorders of hippocampal synaptic plasticity in rotenone-induced PD rats. Furthermore, inhibition of the hippocampal Warburg effect by 2-deoxyglucose abolished NaHS-enhanced hippocampal synaptic plasticity and reversed NaHS-attenuated depression-like behaviours in the rotenone-induced PD rats. ConclusionH2S attenuates PD-associated depression by improving the hippocampal synaptic plasticity in a hippocampal Warburg effect-dependent manner.

The environmental enrichment ameliorates chronic cerebral hypoperfusion-induced cognitive impairment by activating autophagy signaling pathway and improving synaptic function in hippocampus

BackgroundChronic cerebral hypoperfusion (CCH) is a frequently observed underlying pathology of both Alzheimer's disease (AD) and vascular dementia (VD), which is a common consequence of cerebral blood flow (CBF) dysregulation. Synaptic damage has been proven as a crucial causative factor for CCH-related cognitive impairment. This study aimed to investigate the neuroprotective impact of environmental enrichment (EE) intervention on CCH-induced synaptic destruction and the consequent cognitive impairment. Furthermore, the underlying mechanism of this neuroprotective effect was explored to provide new insights into therapeutic interventions for individuals suffering from AD or VD. MethodsIn this experiment, all rats were initially acclimatized to a standard environment (SE) for a period of one week. On the seventh day, rats underwent either bilateral common carotid artery occlusion (2VO) surgery or sham surgery (Sham) before being subjected to a four-week procedure of exposure to an EE, except for the control group. During the EE or SE procedure, intraperitoneal injection of chloroquine (CQ) into rats was performed once daily for four weeks. Following this, cognitive function was assessed using the Morris water maze (MWM) test. The synapse ultrastructure was subsequently observed using transmission electron microscopy. Expression levels of autophagy-related proteins (LC3, LAMP1, and P62) and synapse-related proteins (Synapsin I and PSD-95) were detected through Western blotting. Finally, immunofluorescence was used to examine the expression levels of Synapsin I and PSD-95 and the colocalization of LAMP-1 and LC3 in the hippocampus. ResultsAfter undergoing 2VO, rats exposed to SE exhibited cognitive impairment, autophagic dysfunction, and synapse damage. The synapse damage was evidenced by ultrastructural damage and degradation of synapse-related proteins. However, these effects were significantly mitigated by exposure to an EE intervention. Moreover, the intervention led to an improvement in autophagic dysfunction. ConclusionThe study found that EE had a positive impact on CCH-induced synaptic damage. Specifically, EE was found to increase synaptic plasticity-associated proteins and postsynaptic density thickness, while decreasing synaptic space. This multifaceted effect resulted in an amelioration of CCH-induced cognitive impairment. It was shown that this beneficial outcome was mediated via the activation of the autophagy-lysosomal pathway. Overall, the findings suggest that EE may have a therapeutic potential for cognitive impairments associated with CCH through autophagy-mediated synaptic improvement.

Long-term spaceflight composite stress induces depressive behaviors in model rats through disrupting hippocampus synaptic plasticity.

Long-term spaceflight composite stress (LSCS) can cause adverse effects on human systems, including the central nervous system, which could trigger anxiety and depression. This study aimed to identify changes in hippocampus synaptic plasticity under LSCS. The present study simulated the real long-term space station environment by conducting a 42-day experiment that involved simulating microgravity, isolation, noise, circadian rhythm disruptions, and low pressure. The mood and behavior of the rats were assessed by behavior test. Transmission electron microscopy and patch-clamp were used to detect the changes in synapse morphology and electrophysiology, and finally, the expression of NMDA receptor channel proteins was detected by western blotting. The results showed that significant weight loss, anxiety, and depressive behaviors in rats were observed after being exposed to LSCS environment for 42 days. The synaptic structure was severely damaged, manifested as an obvious decrease in postsynaptic density thickness and synaptic interface curvature (p < 0.05; p < 0.05, respectively). Meanwhile, LTP was significantly impaired (p < 0.0001), and currents in the NMDAR channel were also significantly reduced (p < 0.0001). Further analysis found that LSCS decreased the expression of two key subtype proteins on this channel. These results suggested that LSCS-induced depressive behaviors by impairing synaptic plasticity in rat hippocampus.

Activation of p38 MAPK hinders the reactivation of visual cortical plasticity in adult amblyopic mice

ObjectiveTo investigate the impact of p38 mitogen-activated protein kinase (MAPK) signaling on reactivating visual cortical plasticity in adult amblyopic mice. Materials and methodsReverse suture (RS), environment enrichment (EE), and combined with left intracerebroventricular injection of p38 MAPK inhibitor (SB203580, SB) or p38 MAPK agonist (dehydrocorydaline hydrochloride, DHC) were utilized to treat adult amblyopic mice with monocular deprivation (MD). The visual water task, visual cliff test, and Flash visual-evoked potential were used to measure the visual function. Then, Golgi staining and transmission electron microscopy were used to assess the reactivation of structural plasticity in adult amblyopic mice. Western blot and immunohistochemistry detected the expression of ATF2, PSD-95, p38 MAPK, and phospho-p38 MAPK in the left visual cortex. ResultsNo statistically significant difference was observed in the visual function in each pre-intervention group. Compared to pre-intervention, the visual acuity of deprived eyes was improved significantly, the impairment of visual depth perception was alleviated, and the P wave amplitude and C/I ratio were increased in the EE + RS, the EE + RS + SB, and the EE + RS + DMSO groups, but no significant difference was detected in the EE + RS + DHC group. Compared to EE + RS + DHC group, the density of dendritic spines was significantly higher, the synaptic density of the left visual cortex increased significantly, the length of the active synaptic zone increased, and the thickness of post-synaptic density (PSD) thickened in the left visual cortex of EE + RS, EE + RS + SB, and EE + RS + DMSO groups. And that, the protein expression of p-p38 MAPK increased while that of PSD-95 and ATF2 decreased significantly in the left visual cortex of the EE + RS + DHC group mice. ConclusionRS and EE intervention improved the visual function and synaptic plasticity of the visual cortex in adult amblyopic mice. However, activating p38 MAPK hinders the recovery of visual function by upregulating the phosphorylation of p38 MAPK and decreasing the ATF2 protein expression.

Exercise-with-melatonin therapy improves sleep disorder and motor dysfunction in a rat model of ischemic stroke.

Abstract JOURNAL/nrgr/04.03/01300535-202406000-00038/inline-graphic1/v/2023-10-30T152229Z/r/image-tiff Exercise-with-melatonin therapy has complementary and synergistic effects on spinal cord injury and Alzheimer’s disease, but its effect on stroke is still poorly understood. In this study, we established a rat model of ischemic stroke by occluding the middle cerebral artery for 60 minutes. We treated the rats with exercise and melatonin therapy for 7 consecutive days. Results showed that exercise-with-melatonin therapy significantly prolonged sleep duration in the model rats, increased delta power values, and regularized delta power rhythm. Additionally, exercise-with-melatonin therapy improved coordination, endurance, and grip strength, as well as learning and memory abilities. At the same time, it led to higher hippocampal CA1 neuron activity and postsynaptic density thickness and lower expression of glutamate receptor 2 than did exercise or melatonin therapy alone. These findings suggest that exercise-with-melatonin therapy can alleviate sleep disorder and motor dysfunction by increasing glutamate receptor 2 protein expression and regulating hippocampal CA1 synaptic plasticity.

Activation of the Hippocampal DRD2 Alleviates Neuroinflammation, Synaptic Plasticity Damage and Cognitive Impairment After Sleep Deprivation.

Sleep loss is commonplace nowadays and profoundly impacts cognition. Dopamine receptor D2 (DRD2) makes a specific contribution to cognition, although the precise mechanism underlying how DRD2 affects the cognitive process after sleep deprivation remains unclear. Herein, we observed cognitive impairment and impaired synaptic plasticity, including downregulation of synaptophysin and PSD95, decreased postsynaptic density thickness, neuron complexity, and spine density in chronic sleep restriction (CSR) mice. We also observed downregulated hippocampal DRD2 and Cryab expression in the CSR mice. Meanwhile, NF-κB translocation from the cytoplasm to the nucleus occurred, indicating that neuroinflammation ensued. However, hippocampal delivery of the DRD2 agonist quinpirole effectively rescued these changes. In vitro, quinpirole treatment significantly decreased the release of proinflammatory cytokines in microglial supernatant, indicating a potential anti-neuroinflammatory effect of Drd2/Cryab/NF-κB in CSR mice. Our study provided the evidence that activation of the Drd2 may relieve neuroinflammation and improve sleep deprivation-induced cognitive deficits.

Regulatory role of the p38 MAPK/ATF2 signaling pathway in visual function and visual cortical plasticity in mice with monocular deprivation

BackgroundThis study aimed to examine the role of the p38 mitogen-activated protein kinase (MAPK)/ activating transcription factor 2 (ATF2) signaling in visual function impairment and visual cortical plasticity in mice with monocular deprivation (MD). MethodsVisual behavioral tests, including visual water task, visual cliff test, and flash visual evoked potential, were performed on each group. We studied the density of dendritic spines and the synaptic ultrastructure by Golgi staining and transmission electron microscope. We performed Western blot and immunohistochemistry and detected the expression of ATF2, PSD-95, p38 MAPK, and phosphor-p38 MAPK in the left visual cortex. ResultsIn the MD + SB group, the visual acuity in deprived eyes substantially improved, the impairment of visual depth perception was alleviated, and the P wave amplitude and C/I ratio increased. The density of dendritic spines and the numerical density of synapses increased significantly, the width of the synaptic cleft decreased significantly, and the length of the active synaptic zone and the thickness of post-synaptic density (PSD) increased substantially. The protein expression of phosphor-p38 MAPK decreased, whereas that of PSD-95 and ATF2 increased significantly. ConclusionsInhibiting the phosphorylation of p38 MAPK and negative feedback upregulated ATF2 expression, alleviated damage to visual function, and protected against synaptic plasticity in mice with MD.

Kidney Yang Deficiency Syndrome Exacerbates Aβ25-35-Induced Pathological Changes, and Ginsenoside Re Ameliorates Synapse Lesions in Aβ25-35- Injected Rats with Kidney Yang Deficiency Syndrome.

Traditional Chinese medicine (TCM) indicates that Alzheimer's disease (AD) is considered the consequence produced by Kidney Yang Deficiency Syndrome (KDS-Yang), which has similar clinical characteristics to glucocorticoid withdrawal syndrome. Ginsenoside Re (G-Re) has been found to ameliorate the symptoms and pathological impairments of AD. However, it's not clear whether G-Re could protect memory and synapse lesions against kidney deficiency dementia. Subcutaneous injection of hydrocortisone for 14 days was used to produce KDS-Yang. On the 15th day, Aβ25-35 peptide was injected into the intracerebroventricular (icv) of KDS-Yang rats. Spine density was analyzed by Golgi staining and the ultrastructural morphology of the synapse was detected using Transmission Electron Microscopy (TEM). Western blot was used to examine the expression of pS396, pS404, Tau-5, tGSK-3β, pS9GSK-3β, Syt, Syn I, GluA1, GluN2B, PSD93, PSD95, β2-AR and pS346-b2-AR. Hyperphosphorylation of tau in Aβ25-35-injected rats with KDS-Yang was stronger than in Aβ25-35-injected rats at the sites of Ser396 and Ser404. G-Re improved spatial memory damage detected by Morris water-maze (MWM), enhanced spines density, the thickness of postsynaptic density (PSD) and increased the expression of Syt, Syn I, GluA1, GluN2B, PSD93 and PSD95. Moreover, GRe decreased the hyperphosphorylation of β2-AR at serine 346 in Aβ25-35-injected rats with KDS-Yang. KDS-Yang might exacerbate AD pathological lesions. Importantly, G-Re is a potential ingredient for protecting against memory and synapse deficits in kidney deficiency dementia.

Efficacy of Baishao Luoshi decoction on synaptic plasticity in rats with post stroke spasticity.

To evaluate the efficacy of Baishao Luoshi decoction (, BD) on synaptic plasticity in rats with post stroke spasticity (PSS), and to study the mechanism behind the action. The PSS model of rat was established by middle cerebral artery occlusion (MCAO). The neurological deficit symptoms were evaluated by modified neurological deficit score (mNSS). Muscle tension were evaluated by Modified Ashworth score (MAS). Transmission electron microscopy (TEM) was used to observe the synaptic ultrastructure. The expression of synaptic plasticity-related protein brain derived neurotrophic factor (BDNF), growth associated protein-43 (GAP43), synaptophysin (p38) and microtubule-associated protein 2 (MAP2) in the brain tissue around the infarct were detected by Western blotting. We found that mNSS were significantly improved and limb spasticity was ameliorated treated by BD. The thickness of postsynaptic density and the synaptic curvature increased significantly. The expression of synaptic plasticity-related protein BDNF, GAP43, p38, MAP2 in the brain tissue around the infarct were raised remarkably after treated by BD. Alleviating PSS by BD may be related to rescuing the synaptic plasticity, which provides a probable new therapeutic method for PSS.

Role of miR-219a-5p in regulating NMDAR in nonylphenol-induced synaptic plasticity damage

Nonylphenol (NP) is a typical environmental endocrine disruptor with estrogenic effects. It serves as an emulsifier and as the main ingredient of detergents and has become an increasingly common pollutant in both fresh and salt water, vegetables, and fruits. This study aimed to clarify whether NP exposure could lead to cognitive dysfunction and synaptic plasticity impairment, and also explore the mechanism of microRNA (miR)− 219a-5p regulation of N-methyl-D-aspartate receptor (NMDAR) in NP-induced synaptic plasticity impairment in vivo and in vitro. In vivo, 30 male Sprague–Dawley rats were randomly divided into 2 groups: blank control group (pure corn oil) and NP-exposed group [NP 80 mg/(kg·d)], with 15 rats in each group. In vitro, the extracted hippocampal neurons were divided into 6 groups: blank control group, mimics NC group, miR-219 mimics group, NP group (70 μmol/L NP), NP + mimics NC group, and NP + miR-219 mimics group. In vivo, the content of NP in hippocampal tissues after 90 days of NP exposure was significantly higher in the NP-stained group than in the blank control group. NP exposure could lead to a decrease in the ability to learn and memory, ability to remember, and space spatial memory ability in rats. The dendrites in the NP-stained group were disordered, with few dendritic spines and significantly decreased dendritic spine density. The postsynaptic densities were loosely arranged, the thickness and length of the postsynaptic densities shortened, and the length and width of the synaptic gap increased. Glutamine (Glu) and γ-aminobutyric acid (GABA) contents in hippocampal tissues decreased in the NP-stained group. The expression of miR-219a-5p mRNA decreased in the NP-stained group after 3 months of NP exposure. The expression of NMDAR1, NMDAR2A, NMDAR2B, nerve growth–associated protein (GAP-43), and Ca/calmodulin-dependent kinase II (CaMKII) mRNA/proteins decreased in the NP-stained group. In vitro, NMDAR protein expression decreased, while GAP-43 and CaMKII protein expression increased in the miR-219 mimics group compared with the control group. The expression levels of NMDAR and GAP-43 and CaMKII proteins were higher in the NP + miR-219 mimics group compared with the NP group. The levels of neurotransmitters Glu and GABA decreased in the NP and NP + mimics NC groups compared with the blank group. Shortened synaptic active band length, decreased thickness of postsynaptic densities, and shortened length of postsynaptic densities were observed in the NP, NP + mimics NC, and NP + miR-219 mimics groups compared with the blank control group. In vivo, NP exposure reduced learning memory capacity and neurotransmitter content in rats and caused a decrease in dendritic spine density and synaptic number density and a decrease in miR-219a-5p expression. In vitro, high expression of miR-219a-5p inhibited the expression of NMDAR, thus reducing the effect of NP on synaptic plasticity impairment in hippocampal neurons. Our study provided a scientific basis for the prevention of cognitive impairment owing to NP exposure and the development of targeted drug treatment strategies.

Altered synaptic protein expression, aberrant spine morphology, and impaired spatial memory in Dlgap2 mutant mice, a genetic model of autism spectrum disorder.

A microdeletion of approximately 2.4Mb at the 8p23 terminal region has been identified in a Taiwanese autistic boy. Among the products transcribed/translated from genes mapped in this region, the reduction of DLGAP2, a postsynaptic scaffold protein, might be involved in the pathogenesis of autism spectrum disorder (ASD). DLGAP2 protein was detected in the hippocampus yet abolished in homozygous Dlgap2 knockout (Dlgap2 KO) mice. In this study, we characterized the hippocampal phenotypes in Dlgap2 mutant mice. Dlgap2 KO mice exhibited impaired spatial memory, indicating poor hippocampal function in the absence of DLGAP2. Aberrant expressions of postsynaptic proteins, including PSD95, SHANK3, HOMER1, GluN2A, GluR2, mGluR1, mGluR5, βCAMKII, ERK1/2, ARC, BDNF, were noticed in Dlgap2 mutant mice. Further, the spine density was increased in Dlgap2 KO mice, while the ratio of mushroom-type spines was decreased. We also observed a thinner postsynaptic density thickness in Dlgap2 KO mice at the ultrastructural level. These structural changes found in the hippocampus of Dlgap2 KO mice might be linked to impaired hippocampus-related cognitive functions such as spatial memory. Mice with Dlgap2 deficiency, showing signs of intellectual disability, a common co-occurring condition in patients with ASD, could be a promising animal model which may advance our understanding of ASD.

Neuroprotective Effects of Estrogen Through BDNF-Transient Receptor Potential Channels 6 Signaling Pathway in the Hippocampus in a Rat Model of Perimenopausal Depression.

Estradiol (E2) has been proven to be effective in treating perimenopausal depression (PD); however, the downstream signaling pathways have not been fully elucidated. Transient receptor potential channels 6 (TRPC6) plays a vital role in promoting neuronal development and the formation of excitatory synapses. At present, we found that the serum levels of E2 and brain-derived neurotrophic factor (BDNF) declined significantly in the women with PD compared to perimenopausal women, which was accompanied by a clear reduction in TRPC6 levels. To further reveal the effects of TRPC6 on neuronal survival and excitability, the PD-like rat model was established by the total removal of left ovary and 80% removal of right ovary followed by 21 days of the chronic unpredictable mild stress. Intragastric administration of E2 (2 mg/kg), intraperitoneal injection of BDNF/TrB signaling pathway inhibitor (K252a, 100 μg/kg) and TRPC6 agonist (OAG, 0.6 mg/kg), and intracerebroventricular infusion of anti-BDNF antibody for blocking BDNF (0.5 μg/24 μl/rat) daily for 21 days were conducted. The levels of BDNF and TRPC6 in rat serum were lower in PD rats compared to the control rats; the depression-like behavior was induced, the neuronal death rate in the hippocampus increased, and the thickness of postsynaptic density (PSD) and the number of asymmetric synapses decreased significantly in the PD group. E2 treatment greatly upregulated the serum levels of BDNF and TRPC6, the neuronal excitability indicated by an elevation in the PSD thickness and the numbers of asymmetric synapses, and these actions were reversed by K252a; co-administration of TRPC6 agonist and K252a improved neuronal degeneration and increased the neuronal excitability induced in the E2-treated PD rats. K252a or anti-BDNF antibody inhibited the increased neuronal BDNF and TRPC6 expression in E2-treated PD rats; co-treatment of TRPC6 agonist and anti-BDNF antibody reduced neuronal death and increased the BDNF and TRPC6 expression in the hippocampal CA1 neurons in the E2-treated PD rats. These results suggest that the neuroprotective role of E2 in PD is closely related to enhance the activity of BDNF/TRPC6 pathway and is helpful to provide new prevention and strategies.

Dendrobium nobile Lindl. Alkaloids Ameliorate Aβ25-35-Induced Synaptic Deficits by Targeting Wnt/β-Catenin Pathway in Alzheimer's Disease Models.

Dendrobium nobile Lindl. alkaloids (DNLA) are effective in ameliorating cognitive deficit in SAMP8, AβPP/PS1, and LPS-induced AD animal models, and prevented Aβ-induced synaptic degeneration in cultured hippocampal neurons. However, the underlying mechanisms remain unexplored. This study investigated the protective effects of DNLA on synaptic damage in an Aβ25-35-induced rat AD model, in primary cortical neuron cultures, and in PC12 cells transfected with human AβPP695, focusing on the Wnt/β-catenin pathway. Sprague-Dawley rats received a single Aβ25-35 injection (10μg) into the bilateral hippocampi. DNLA (40 and 80 mg/kg/d) was intragastrically administrated 7 days prior to Aβ injection and continued for 28 days. The spatial learning and memory, synaptic morphology, synapse-related proteins, and Wnt signaling components GSK3β and β-catenin phosphorylation were evaluated. Rat primary cortical neuron cultures and AβPP695-PC12 cells were used to evaluate axonal mitochondria distribution, reactive oxygen species production, amyloidogenesis, and Wnt pathway in the protection. DNLA ameliorated Aβ-induced cognitive impairment, increased the number of synapses, elevated the postsynaptic density thickness and expression of synapsin and PSD95 in the hippocampus, and suppressed Aβ-mediated GSK3β activity and the β-catenin phosphorylation. In primary neurons and AβPP695-PC12 cells, DNLA restored Aβ25-35 induced mitochondrial dysfunction and inhibited reactive oxygen species production and amyloidogenesis. Furthermore, the Wnt/β-catenin pathway inhibitor Dkk-1 blocked the effect of DNLA on the expression of Aβ1-42 and PSD95. DNLA rescued Aβ-mediated synaptic and mitochondrial injury and inhibited amyloidogenesis in vivo and in vitro, probably through the activation of Wnt/β-catenin signaling pathway to protect synaptic integrity.

Administration of miR-195 Inhibitor Enhances Memory Function Through Improving Synaptic Degradation and Mitochondrial Dysfunction of the Hippocampal Neurons in SAMP8 Mice.

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD) and miR-195 is involved in mitochondrial disorder through targeting MFN-2 protein in hippocampal neurons of AD. To clarify if administration of miR-195 inhibitor could enhance the memory deficits through improving hippocampal neuron mitochondrial dysfunction in SAMP8 mice. The expression of miR-195 was detected by RT-qPCR in primary hippocampal neurons and HT-22 cells treated with Aβ1-42. Morris water maze (MWM) was used to assess the learning and memory function in SAMP8 mice administrated with antagomir-195. Transmission electron microscopy was employed to determine the morphological changes of synapses and mitochondria of hippocampus in SAMP8 mice. Mitochondrial respiration was measured using a high-resolution oxygraph. The expression of miR-195 were upregulated in the primary hippocampal neurons and HT-22 cells induced by Aβ1-42. Inhibition of miR-195 ameliorated the mitochondrial dysfunction in HT-22 cells induced by Aβ1-42, including mitochondrial morphologic damages, mitochondrial membrane potential, respiration function, and ATP production. Administration of antagomir-195 by the third ventricle injection markedly ameliorated the cognitive function, postsynaptic density thickness, length of synaptic active area, mitochondrial aspect ratio, and area in hippocampus of SAMP8 mice. Finally, antagomir-195 was able to promote an increase in the activity of respiratory chain complex CI and II in SAMP8 mice. This study demonstrated that miR-195 inhibitor ameliorated the cognitive impairment of AD mice by improving mitochondrial structure damages and dysfunction in the hippocampal neurons, which provide an experimental basis for further exploring the treatment strategy of AD.

A schizophrenia risk factor induces marked anatomical deficits at GABAergic-dopaminergic synapses in the rat ventral tegmental area: Essential evidence for new targeted therapies.

To develop new therapies for schizophrenia, evidence accumulated over decades highlights the essential need to investigate the GABAergic synapses that presynaptically influence midbrain dopaminergic neurons. Since current technology restricts these studies to animals, and evidence accumulated in recent decades indicates a developmental origin of schizophrenia, we investigated synaptic changes in male rat offspring exposed to maternal immune activation (MIA), a schizophrenia risk factor. Using a novel combination of lentiviruses, peroxidase-immunogold double labeling, three-dimensional serial section transmission electron microscopy and stereology, we observed clear anatomical alterations in synaptic inputs on dopaminergic neurons in the midbrain posterior ventral tegmental area (pVTA). These changes relate directly to a characteristic feature of schizophrenia: increased dopamine release. In 3-month-old and 14-month-old MIA rats, we found a marked decrease in the volume of presynaptic GABAergic terminals from the rostromedial tegmental nucleus (RMTg) and in the length of the synapses they made, when innervating pVTA dopaminergic neurons. In MIA rats in the long-term, we also discovered a decrease in the volume of the postsynaptic density (PSD) and in the maximum thickness of the PSD at the same synapses. These marked deficits were evident in conventional GABA-dopamine synapses and in synaptic triads that we discovered involving asymmetric synapses that innervated RMTg GABAergic presynaptic terminals, which in turn innervated pVTA dopaminergic neurons. In triads, the PSD thickness of asymmetric synapses was significantly decreased in MIA rats in the long-term cohort. The extensive anatomical deficits provide a potential basis for new therapies targeted at synaptic inputs on midbrain pVTA dopaminergic neurons, in contrast to current striatum-targeted antipsychotic drugs.

Treadmill exercise overcomes memory deficits related to synaptic plasticity through modulating ionic glutamate receptors

Neuronal death and synaptic loss are major pathogensis of Alzheimer’s disease (AD), which may be related to the ionic glutamate receptors abnormality. Ionic glutamate receptors are important postsynaptic membrane receptors that regulate excitatory synaptic transmission and are also major component of the postsynaptic density. Beta-Amyloid (Aβ) attacks ionic glutamate receptors to reduce synaptic efficacy and synaptic plasticity, resulting in neuronal death and synaptic loss. The current study aimed to investigate whether exercise-ameliorated AD was associated with changes in ionic glutamate receptors. Transgenic APP/PS1 mice (TgAPP/PS1) and age-matched littermate wild mice were divided into wild type control group, wild type exercise group, transgenic control group and transgenic exercise group. The mice in exercise groups were subjected to treadmill training for 12 weeks. The results showed that 12-week treadmill exercise improved the spatial learning and memory abilities of TgAPP/PS1 mice. Moreover, exercise decreased the contents of Aβ40, Aβ42 and amyloid plaque deposition in hippocampus of TgAPP/PS1 mice. The number of synapses and the length and thickness of postsynaptic densities (PSD) in the hippocampal CA1 region of TgAPP/PS1 mice were significantly increased after exercise. Concomitantly, TgAPP/PS1 displayed obstacles in synaptic plasticity as evidenced by significant decreases in the levels of synaptic structural plasticity-related proteins SYN, PSD95, MAP2 and NCAM, as well as ionic glutamate neuroreceptor subunit proteins GluN2B and GluA1. Interestingly, exercise alleviated these synaptic plasticity disorder in TgAPP/PS1 mice. Thus, this study demonstrates that 12-week treadmill exercise reduces Aβ levels in the hippocampus and mitigates cognitive decline in TgAPP/PS1 mice, which may be mediated by improvements in synaptic structural plasticity and excitatory neurotransmission.