GDNF facilitates cognitive function recovery following neonatal surgical-induced learning and memory impairment via activation of the RET pathway and modulation of downstream effectors PKMζ and Kalirin in rats.

OBJECTIVE: The aim of this study is to elucidate the underlying mechanism through which glial cell line-derived neurotrophic factor (GDNF) improves cognitive deficits in adults resulting from neonatal surgical interventions. METHODS: Newborn Sprague-Dawley rats, regardless of gender, were randomly allocated into seven groups on postnatal day 7 as follows (n=15): (1) Control group (not subjected to anesthesia, surgery, or any pharmaceutical interventions); (2) GDNF group (received intracerebroventricular injection of GDNF); (3) Surgery group (underwent right carotid artery exposure under anesthesia with 3 % sevoflurane); (4) Surgery plus GDNF group; (5) Surgery plus GDNF and type II JAK inhibitor NVP-BBT594 (BBT594) group (administered intraperitoneal injection of BBT594); (6) BBT group; and (7) Surgery plus BBT group. Starting from postnatal day 33, all rats underwent Barnes maze and fear conditioning tests, followed by decapitation under sevoflurane anesthesia for subsequent analyses. The left hemibrains underwent Golgi staining, while the right hemibrains were used for hippocampal protein extraction to assess Protein kinase Mζ (PKMζ) and Kalirin expression through western blotting. RESULTS: GDNF demonstrated a mitigating effect on spatial learning and memory impairment, as well as context-related fear memory impairment, reductions in dendritic total lengths, and spinal density within the hippocampus induced by surgical intervention. Notably, all of these ameliorative effects of GDNF were reversed upon administration of the RET inhibitor BBT594. Additionally, GDNF alleviated the downregulation of protein expression of PKMζ and Kalirin in the hippocampus of rats subjected to surgery, subsequently reversed by BBT594. CONCLUSION: The effective impact of GDNF on learning and memory impairment caused by surgical intervention appears to be mediated through the RET pathway. Moreover, GDNF may exert its influence by upregulating the expression of PKMζ and Kalirin, consequently enhancing the development of dendrites and dendritic spines.

Promising therapeutic effects of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in addressing autism spectrum disorder induced by valproic acid.

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects various regions of the brain. Repetitive transcranial magnetic stimulation (rTMS) is a safe and non-invasive method utilized for stimulating different brain areas. Our objective is to alleviate ASD symptoms using high-frequency rTMS (HF-rTMS) in a rat model of ASD induced by valproic acid (VPA). Methods: In this investigation, we applied HF-rTMS for ASD treatment, focusing on the hippocampus. Behavioral assessments encompassed core ASD behaviors, as well as memory and recognition tests, alongside evaluations of anxiety and stress coping strategies. Additionally, we analyzed oxidative stress and a related inflammation marker, as well as other biochemical components. We assessed brain-derived neurotrophic factor (BDNF), Microtubule-associated protein-2 (MAP-2), and synaptophysin (SYN). Finally, we examined dendritic spine density in the CA1 area of the hippocampus. Results: The results demonstrated that HF-rTMS successfully mitigated ASD symptoms, reducing oxidative stress and improving various biochemical factors, along with an increase in dendritic spine density. Discussion: Collectively, our data suggests that HF-rTMS may effectively alleviate ASD symptoms. These findings could be valuable in clinical research and contribute to a better understanding of the mechanisms underlying ASD.

Toward the development of a sporadic model of Alzheimer's disease: comparing pathologies between humanized APP and the familial J20 mouse models.

Background: Finding successful therapies for individuals with Alzheimer's disease (AD) remains an ongoing challenge. One contributing factor is that the mouse models commonly used in preclinical research primarily mimic the familial form of AD, whereas the vast majority of human cases are sporadic. Accordingly, for a sporadic mouse model of AD, incorporating the multifactorial aspects of the disease is of utmost importance. Methods: In the current study, we exposed humanized Aß knock-in mice (hAß-KI) to weekly low-dose lipopolysaccharide (LPS) injections until 24 weeks of age and compared the development of AD pathologies to the familial AD mouse model known as the J20 mice. Results: At the early time point of 24 weeks, hAß-KI mice and J20 mice exhibited spatial memory impairments in the Barnes maze. Strikingly, both hAß-KI mice and J20 mice showed significant loss of dendritic spines when compared to WT controls, despite the absence of Aß plaques in hAß-KI mice at 24 weeks of age. Glial cell numbers remained unchanged in hAß-KI mice compared to WT, and LPS exposure in hAß-KI mice did not result in memory deficits and failed to exacerbate any other examined AD pathology. Conclusion: The study highlights the potential of hAß-KI mice as a model for sporadic AD, demonstrating early cognitive deficits and synaptic alterations despite no evidence of Aß plaque formation. These findings underscore the importance of considering multifactorial influences in sporadic AD pathogenesis and the need for innovative models to advance our understanding and treatment strategies for this complex disease.

PolyI:C Maternal Immune Activation on E9.5 Causes the Deregulation of Microglia and the Complement System in Mice, Leading to Decreased Synaptic Spine Density.

Maternal immune activation (MIA) is a risk factor for multiple neurodevelopmental disorders; however, animal models developed to explore MIA mechanisms are sensitive to experimental factors, which has led to complexity in previous reports of the MIA phenotype. We sought to characterize an MIA protocol throughout development to understand how prenatal immune insult alters the trajectory of important neurodevelopmental processes, including the microglial regulation of synaptic spines and complement signaling. We used polyinosinic:polycytidylic acid (polyI:C) to induce MIA on gestational day 9.5 in CD-1 mice, and measured their synaptic spine density, microglial synaptic pruning, and complement protein expression. We found reduced dendritic spine density in the somatosensory cortex starting at 3-weeks-of-age with requisite increases in microglial synaptic pruning and phagocytosis, suggesting spine density loss was caused by increased microglial synaptic pruning. Additionally, we showed dysregulation in complement protein expression persisting into adulthood. Our findings highlight disruptions in the prenatal environment leading to alterations in multiple dynamic processes through to postnatal development. This could potentially suggest developmental time points during which synaptic processes could be measured as risk factors or targeted with therapeutics for neurodevelopmental disorders.

Repopulated microglia after pharmacological depletion decrease dendritic spine density in adult mouse brain.

Microglia are innate immune cells in the brain and show exceptional heterogeneity. They are key players in brain physiological development regulating synaptic plasticity and shaping neuronal networks. In pathological disease states, microglia-induced synaptic pruning mediates synaptic loss and targeting microglia was proposed as a promising therapeutic strategy. However, the effect of microglia depletion and subsequent repopulation on dendritic spine density and neuronal function in the adult brain is largely unknown. In this study, we investigated whether pharmacological microglia depletion affects dendritic spine density after long-term permanent microglia depletion and after short-term microglia depletion with subsequent repopulation. Long-term microglia depletion using colony-stimulating-factor-1 receptor (CSF1-R) inhibitor PLX5622 resulted in increased overall spine density, especially of mushroom spines, and increased excitatory postsynaptic current amplitudes. Short-term PLX5622 treatment with subsequent repopulation of microglia had an opposite effect resulting in activated microglia with increased synaptic phagocytosis and consequently decreased spine density and reduced excitatory neurotransmission, while Barnes maze and elevated plus maze testing was unaffected. Moreover, RNA sequencing data of isolated repopulated microglia showed an activated and proinflammatory phenotype. Long-term microglia depletion might be a promising therapeutic strategy in neurological diseases with pathological microglial activation, synaptic pruning, and synapse loss. However, repopulation after depletion induces activated microglia and results in a decrease of dendritic spines possibly limiting the therapeutic application of microglia depletion. Instead, persistent modulation of pathological microglia activity might be beneficial in controlling synaptic damage.

Social hierarchy differentially influences the anxiety-like behaviors and dendritic spine density in prefrontal cortex and limbic areas in male rats.

Social hierarchy is a fundamental feature of social organization that can influence brain and emotional processing regarding social ranks. Several areas, including the medial prefrontal cortex (mPFC), the hippocampus, and the basolateral nucleus of the amygdala (BLA), are recognized to be involved in the regulation of emotional processing. However, its delicate structural correlates in brain regions are poorly understood. To address this issue, social hierarchy in home-caged sibling Wistar rats (three male rats/cage) was determined by employing a social confrontation tube test (postnatal weeks 9-12). Then, locomotor activity and anxiety-like behaviors were evaluated using an open-field test (OFT) and elevated plus-maze (EPM) at 13 weeks of age. The rapid Golgi impregnation method was conducted to quantify the spine density of the first secondary branch of the primary dendrite in 20 µm length. The results indicated that dominant rats had significantly higher anxiety-like behaviors compared to subordinates, as was evident by lower open-arm entries and time spent in the EPM and lower entries and time spent in the center of OFT. The spine density analysis revealed a significantly higher number of spines in subordinates compared to the dominant rats in dmPFC pyramidal neurons and the apical and basal dendrites of hippocampal CA1 pyramidal neurons. However, the spine density of pyramidal-like neurons in the BLA was higher in dominant rats. Our findings suggest that dominant social rank is associated with higher anxiety and differential density of the dendritic spine in the prefrontal cortex and limbic regions of the brain in male rats.

Modeling sporadic Alzheimer's disease in mice by combining Apolipoprotein E4 risk gene with environmental risk factors.

Introduction: Developing effective treatment for Alzheimer's disease (AD) remains a challenge. This can be partially attributed to the fact that the mouse models used in preclinical research largely replicate familial form of AD, while majority of human cases are sporadic; both forms differ widely in the onset and origin of pathology, therefore requiring specific/targeted treatments. Methods: In this study, we aimed to model sporadic AD in mice by combining two of the many risk factors that are strongly implicated in AD: ApoE4, a major genetic risk factor, together with an inflammatory stimuli. Accordingly, we subjected ApoE4 knock in (KI) mice, expressing humanized ApoE4, to low doses of Lipopolysaccharide (LPS) injections (i.p, weekly, for 4 months). Results: We assessed these animals for behavioral impairments at 6 months of age using Open Field, Y-maze, and Barnes Maze Test. LPS induced hypoactivity was observed in the Open Field and Y-maze test, whereas spatial learning and memory was intact. We then quantified differences in dendritic spine density, which is a strong correlate of AD. ApoE4KI mice showed a significant reduction in the number of spines after treatment with LPS, whereas there were no obvious differences in the total number of microglia and astrocytes. Discussion: To conclude, in the current study the APoEe4 risk gene increases the vulnerability of hippocampal neurons to inflammation induced spine loss, laying a foundation for an early sporadic AD mouse model.

Investigating the impact of nutritional insufficiency on parahippocampal neurons in domestic chickens, Gallus gallus domesticus.

Over time, scientists have been fascinated by the complex connections among nutrition, brain development, and behavior. It's been well understood that the brain's peak performance relies on having the right nutrients available. Thus, nutritional insufficiency, where an organism lacks vital nutrients crucial for optimal growth and function, can upset the body's balance, potentially triggering stress responses. However, our grasp of how the brain reacts to insufficient nutrition, particularly in avian species like domestic chickens, has shown inconsistencies in our understanding. Domestic chickens have frequently served as subjects for studying memory and learning, primarily focusing on the hippocampus-a region highly responsive to environmental changes. Yet, another critical brain region, the parahippocampal region, integral to memory and spatial cognition, had received relatively little attention concerning the consequences of inadequate nutrition and hydration. To address this knowledge gap, our study sought to investigate the impact of stress induced by nutritional insufficiency on the neuronal cells within the region parahippocampalis in two distinct age groups of domestic chickens, Gallus gallus domesticus: fifteen and thirty days old. We employed the Golgi-Cox-Impregnation technique to explore whether the structural characteristics of neuronal cells, specifically the dendritic spines, underwent changes under transient stressful conditions during these crucial developmental stages. The results were intriguing. Stress evidently induced observable alterations in the dendritic spines of the parahippocampal neuronal cells, with the extent of these changes being age-dependent. In fifteen-day-old chickens, stress prompted substantial modifications in the dendritic spines of parahippocampal multipolar and pyramidal neurons. In contrast, among thirty-day-old chickens, the response to stress was less comprehensive, with only specific parahippocampal multipolar neurons displaying such alterations. These findings underscored the influential role of stress in reshaping the structure of parahippocampal neurons and emphasized the importance of considering age when studying the impact of stress on the brain. Through this research, we aim to enhance our understanding of the intricate interplay between stress, brain structure, and the critical role of adequate nutrition, especially during pivotal developmental stages. Our future research objectives include a deeper investigation into the intracellular events including cellular and molecular mechanisms precipitating these changes and determining whether these alterations have downstream effects on crucial brain functions like learning and memory.

Postweaning stress affects behavior, brain and gut microbiota of adolescent mice in a sex-dependent manner.

Aggression is an instinctive behavior that has been reported to be influenced by early-life stress. However, the potential effects of acute stress during the postweaning period, a key stage for brain development, on defensive aggression and the associated mechanism remain poorly understood. In the present study, aggressive behaviors were evaluated in adolescent mice exposed to postweaning stress. Serum corticosterone and testosterone levels, neural dendritic spine density, and gut microbiota composition were determined to identify the underlying mechanism. Behavioral analysis showed that postweaning stress reduced locomotor activity in mice and decreased defensive aggression in male mice. ELISA results showed that postweaning stress reduced serum testosterone levels in female mice. Golgi staining analysis demonstrated that postweaning stress decreased neural dendritic spine density in the medial prefrontal cortex of male mice. 16S rRNA sequencing results indicated that postweaning stress altered the composition of the gut microbiota in male mice. Combined, these results suggested that postweaning stress alters defensive aggression in male mice, which may be due to changes in neuronal structure as well as gut microbiota composition. Our findings highlight the long-lasting and sex-dependent effects of early-life experience on behaviors.

Early chronic fasudil treatment rescues hippocampal alterations in the Ts65Dn model for down syndrome.

Down syndrome (DS) is the most common genetic disorder associated with intellectual disability. To study this syndrome, several mouse models have been developed. Among the most common is the Ts65Dn model, which mimics most of the alterations observed in DS. Ts65Dn mice, as humans with DS, show defects in the structure, density, and distribution of dendritic spines in the cerebral cortex and hippocampus. Fasudil is a potent inhibitor of the RhoA kinase pathway, which is involved in the formation and stabilization of dendritic spines. Our study analysed the effect of early chronic fasudil treatment on the alterations observed in the hippocampus of the Ts65Dn model. We observed that treating Ts65Dn mice with fasudil induced an increase in neural plasticity in the hippocampus: there was an increment in the expression of PSA-NCAM and BDNF, in the dendritic branching and spine density of granule neurons, as well as in cell proliferation and neurogenesis in the subgranular zone. Finally, the treatment reduced the unbalance between excitation and inhibition present in this model. Overall, early chronic treatment with fasudil increases cell plasticity and eliminates differences with euploid animals.

Polystyrene microplastics induced disturbances in neuronal arborization and dendritic spine density in mice prefrontal cortex.

An increasing use of plastics in daily life leads to the accumulation of microplastics (MPs) in the environment, posing a serious threat to the ecosystem, including humans. It has been reported that MPs cause neurotoxicity, but the deleterious effect of polystyrene (PS) MPs on neuronal cytoarchitectural morphology in the prefrontal cortex (PFC) region of mice brain remains to be established. In the present study, Swiss albino male mice were orally exposed to 0.1, 1, and 10 ppm PS-MPs for 28 days. After exposure, we found a significant accumulation of PS-MPs with a decreased number of Nissl bodies in the PFC region of the entire treated group compared to the control. Morphometric analysis in the PFC neurons using Golgi-Cox staining accompanied by Sholl analysis showed a significant reduction in basal dendritic length, dendritic intersections, nodes, and number of intersections at seventh branch order in PFC neurons of 1 ppm treated PS-MPs. In neurons of 0.1 ppm treated mice, we found only decrease in the number of intersections at the seventh branch order. While 10 ppm treated neurons decreased in basal dendritic length, dendritic intersections, followed by the number of intersections at the third and seventh branch order were observed. As well, spine density on the apical secondary branches along with mRNA level of BDNF was significantly reduced in all the PS-MPs treated PFC neurons, mainly at 1 ppm versus control. These results suggest that PS-MPs exposure affects overall basal neuronal arborization, with the highest levels at 1 and 10 ppm, followed by 0.1 ppm treated neurons, which may be related to the down-regulation of BDNF expression in PFC.

Dendritic reorganization in the hippocampus, anterior temporal lobe, and frontal neocortex of lithium-pilocarpine induced Status Epilepticus (SE).

Status Epilepticus (SE) is a distributed network disorder, which involves the hippocampus and extra-hippocampal structures. Epileptogenesis in SE is tightly associated with neurogenesis, plastic changes and neural network reorganization facilitating hyper-excitability. On the other hand, dendritic spines are known to be the excitatory synapse in the brain. Therefore, dendritic spine dynamics could play an intricate role in these network alterations. However, the exact reason behind these structural changes in SE are elusive. In the present study, we have investigated the aforementioned hypothesis in the lithium-pilocarpine treated rat model of SE. We have examined cytoarchitectural and morphological changes using hematoxylin-eosin and Golgi-Cox staining in three different brain regions viz. CA1 pyramidal layer of the dorsal hippocampus, layer V pyramidal neurons of anterior temporal lobe (ATL), and frontal neocortex of the same animals. We observed macrostructural and layer-wise alteration of the pyramidal layer mainly in the hippocampus and ATL of SE rats, which is associated with sclerosis in the hippocampus. Sholl analysis exhibited partial dendritic plasticity in apical and basal dendrites of pyramidal cells as compared to the saline-treated weight-/age-matched control group. These findings indicate that region-specific alterations in dendritogenesis may contribute to the development of independent epileptogenic networks in the hippocampus, ATL, and frontal neocortex of SE rats.

Theiler's Murine Encephalomyelitis Virus Replicates in Primary Neuron Cultures and Impairs Spine Density Formation.

In this study, we examined infection with the highly neurovirulent GDVII, the less neurovirulent DA strains, and with a mutant DA, which lacks the L* protein (L*-1) involved in viral persistence and demyelinating disease, to analyze the direct effects of Theiler's murine encephalomyelitis virus (TMEV) replication using primary cultures of mouse brain hippocampal neurons. All viruses replicate in cultured neurons, with GDVII having the highest titers and L*-1 the lowest. Accordingly, all were positive for viral antigen staining 3 days postinfection (dpi), and DA and L*-1 were also positive after 12 dpi. NeuN + immunostaining showed an early and almost complete absence of positive cells in cultures infected with GDVII, an approximately 50% reduction in cultures infected with DA, and fewer changes in L*-1 strains at 3 dpi. Accordingly, staining with chloromethyltetramethylrosamine orange (Mitotracker OrangeTM) as a parameter for cell viability showed similar results. Moreover, at 1 dpi, the strain DA induced higher transcript levels of neuroprotective genes such as IFN-Iß, IRF7, and IRF8. At 3 dpi, strains GDVII and DA, but not the L*-1 mutant, showed lower PKR expression. In addition, confocal analysis showed that L*-1-infected neurons exhibited a decrease in spine density. Treatment with poly (I:C), which is structurally related to dsRNA and is known to trigger IFN type I synthesis, reduced spine density even more. These results confirmed the use of mouse hippocampal neuron cultures as a model to study neuronal responses after TMEV infection, particularly in the formation of spine density.

Under the umbrella of depression and Alzheimer's disease physiopathology: Can cannabinoids be a dual-pleiotropic therapy?

Depression and Alzheimer´s disease (AD) are two disorders highly prevalent worldwide. Depression affects more than 300 million people worldwide while AD affects 60-80% of the 55 million cases of dementia. Both diseases are affected by aging with high prevalence in elderly and share not only the main brain affected areas but also several physiopathological mechanisms. Depression disease is already ascribed as a risk factor to the development of AD. Despite the wide diversity of pharmacological treatments currently available in clinical practice for depression management, they remain associated to a slow recovery process and to treatment-resistant depression. On the other hand, AD treatment is essentially based in symptomatology relieve. Thus, the need for new multi-target treatments arises. Herein, we discuss the current state-of-art regarding the contribution of the endocannabinoid system (ECS) in synaptic transmission processes, synapses plasticity and neurogenesis and consequently the use of exogenous cannabinoids in the treatment of depression and on delaying the progression of AD. Besides the well-known imbalance of neurotransmitter levels, including serotonin, noradrenaline, dopamine and glutamate, recent scientific evidence highlights aberrant spine density, neuroinflammation, dysregulation of neurotrophic factor levels and formation of amyloid beta (Aß) peptides, as the main physiopathological mechanisms compromised in depression and AD. The contribution of the ECS in these mechanisms is herein specified as well as the pleiotropic effects of phytocannabinoids. At the end, it became evident that Cannabinol, Cannabidiol, Cannabigerol, Cannabidivarin and Cannabichromene may act in novel therapeutic targets, presenting high potential in the pharmacotherapy of both diseases.

Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice.

General anesthetics are potent neurotoxins when given during early development, causing apoptotic deletion of substantial number of neurons and persistent neurocognitive and behavioral deficits in animals and humans. The period of intense synaptogenesis coincides with the peak of susceptibility to deleterious effects of anesthetics, a phenomenon particularly pronounced in vulnerable brain regions such as subiculum. With steadily accumulating evidence confirming that clinical doses and durations of anesthetics may permanently alter the physiological trajectory of brain development, we set out to investigate the long-term consequences on dendritic morphology of subicular pyramidal neurons and expression on genes regulating the complex neural processes such as neuronal connectivity, learning, and memory. Using a well-established model of anesthetic neurotoxicity in rats and mice neonatally exposed to sevoflurane, a volatile general anesthetic commonly used in pediatric anesthesia, we report that a single 6 h of continuous anesthesia administered at postnatal day (PND) 7 resulted in lasting dysregulation in subicular mRNA levels of cAMP responsive element modulator (Crem), cAMP responsive element-binding protein 1 (Creb1), and Protein phosphatase 3 catalytic subunit alpha, a subunit of calcineurin (Ppp3ca) (calcineurin) when examined during juvenile period at PND28. Given the critical role of these genes in synaptic development and neuronal plasticity, we deployed a set of histological measurements to investigate the implications of anesthesia-induced dysregulation of gene expression on morphology and complexity of surviving subicular pyramidal neurons. Our results indicate that neonatal exposure to sevoflurane induced lasting rearrangement of subicular dendrites, resulting in higher orders of complexity and increased branching with no significant effects on the soma of pyramidal neurons. Correspondingly, changes in dendritic complexity were paralleled by the increased spine density on apical dendrites, further highlighting the scope of anesthesia-induced dysregulation of synaptic development. We conclude that neonatal sevoflurane induced persistent genetic and morphological dysregulation in juvenile rodents, which could indicate heightened susceptibility toward cognitive and behavioral disorders we are beginning to recognize as sequelae of early-in-life anesthesia.

Functional regionalization of the differentiating cerebellar Purkinje cell population occurs in an activity-dependent manner.

Introduction: The cerebellum is organized into functional regions each dedicated to process different motor or sensory inputs for controlling different locomotor behaviors. This functional regionalization is prominent in the evolutionary conserved single-cell layered Purkinje cell (PC) population. Fragmented gene expression domains suggest a genetic organization of PC layer regionalization during cerebellum development. However, the establishment of such functionally specific domains during PC differentiation remained elusive. Methods and results: We show the progressive emergence of functional regionalization of PCs from broad responses to spatially restricted regions in zebrafish by means of in vivo Ca2+-imaging during stereotypic locomotive behavior. Moreover, we reveal that formation of new dendritic spines during cerebellar development using in vivo imaging parallels the time course of functional domain development. Pharmacological as well as cell-type specific optogenetic inhibition of PC neuronal activity results in reduced PC dendritic spine density and an altered stagnant pattern of functional domain formation in the PC layer. Discussion: Hence, our study suggests that functional regionalization of the PC layer is driven by physiological activity of maturing PCs themselves.

Hippocampal BAIAP2 prevents chronic mild stress-induced depression-like behaviors in mice.

Background: The pathogenesis of depression is closely related to changes in hippocampal synaptic plasticity; however, the underlying mechanism is still unclear. Brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2), a postsynaptic scaffold protein in excitatory synapses important for synaptic plasticity, is highly expressed in the hippocampus and has been implicated in several psychiatric disorders. However, the role of BAIAP2 in depression remains poorly understood. Methods: In the present study, a mouse model of depression was established via exposure to chronic mild stress (CMS). An adeno-associated virus (AAV) vector expressing BAIAP2 was injected into the hippocampal brain region of mice and a BAIAP2 overexpression plasmid was transfected into HT22 cells to upregulate BAIAP2 expression. Depression- and anxiety-like behaviors and dendritic spine density were examined in mice using behavioral tests and Golgi staining, respectively. In vitro, hippocampal HT22 cells were treated with corticosterone (CORT) to simulate the stress state, and the effect of BAIAP2 on CORT-induced cell injury was explored. Reverse transcription-quantitative PCR and western blotting were employed to determine the expression levels of BAIAP2 and those of the synaptic plasticity-related proteins glutamate receptor ionotropic, AMPA 1 (GluA1), and synapsin 1 (SYN1). Results: Mice exposed to CMS exhibited depression- and anxiety-like behaviors accompanied by decreased levels of BAIAP2 in the hippocampus. In vitro, the overexpression of BAIAP2 increased the survival rate of CORT-treated HT22 cells and upregulated the expression of GluA1 and SYN1. Consistent with the in vitro data, the AAV-mediated overexpression of BAIAP2 in the hippocampus of mice significantly inhibited CMS-induced depression-like behavior, concomitant with increases in dendritic spine density and the expression of GluA1 and SYN1 in hippocampal regions. Conclusion: Our findings indicate that hippocampal BAIAP2 can prevent stress-induced depression-like behavior and may be a promising target for the treatment of depression or other stress-related diseases.

ERVWE1 Reduces Hippocampal Neuron Density and Impairs Dendritic Spine Morphology through Inhibiting Wnt/JNK Non-Canonical Pathway via miR-141-3p in Schizophrenia.

Human endogenous retroviruses (HERVs) are remnants of ancestral germline infections by exogenous retroviruses. Human endogenous retroviruses W family envelope gene (HERV-W env, also called ERVWE1), located on chromosome 7q21-22, encodes an envelope glycoprotein from the HERV-W family. Mounting evidence suggests that aberrant expression of ERVWE1 involves the etiology of schizophrenia. Moreover, the genetic and morphological studies indicate that dendritic spine deficits may contribute to the onset of schizophrenia. Here, we reported that ERVWE1 changed the density and morphology of the dendritic spine through inhibiting Wingless-type (Wnt)/c-Jun N-terminal kinases (JNK) non-canonical pathway via miR-141-3p in schizophrenia. In this paper, we found elevated levels of miR-141-3p and a significant positive correlation with ERVWE1 in schizophrenia. Moreover, serum Wnt5a and actin-related protein 2 (Arp2) levels decreased and demonstrated a significant negative correlation with ERVWE1 in schizophrenia. In vitro experiments disclosed that ERVWE1 up-regulated miR-141-3p expression by interacting with transcription factor (TF) Yin Yang 1 (YY1). YY1 modulated miR-141-3p expression by binding to its promoter. The luciferase assay revealed that YY1 enhanced the promoter activity of miR-141-3p. Using the miRNA target prediction databases and luciferase reporter assays, we demonstrated that miR-141-3p targeted Wnt5a at its 3' untranslated region (3' UTR). Furthermore, ERVWE1 suppressed the expression of Arp2 through non-canonical pathway, Wnt5a/JNK signaling pathway. In addition, ERVWE1 inhibited Wnt5a/JNK/Arp2 signal pathway through miR-141-3p. Finally, functional assays showed that ERVWE1 induced the abnormalities in hippocampal neuron morphology and spine density through inhibiting Wnt/JNK non-canonical pathway via miR-141-3p in schizophrenia. Our findings indicated that miR-141-3p, Wnt5a, and Arp2 might be potential clinical blood-based biomarkers or therapeutic targets for schizophrenia. Our work also provided new insight into the role of ERVWE1 in schizophrenia pathogenesis.

The Anaesthetics Isoflurane and Xenon Reverse the Synaptotoxic Effects of Aß1-42 on Megf10-Dependent Astrocytic Synapse Elimination and Spine Density in Ex Vivo Hippocampal Brain Slices.

It has been hypothesised that inhalational anaesthetics such as isoflurane (Iso) may trigger the pathogenesis of Alzheimer's disease (AD), while the gaseous anaesthetic xenon (Xe) exhibits many features of a putative neuroprotective agent. Loss of synapses is regarded as one key cause of dementia in AD. Multiple EGF-like domains 10 (MEGF10) is one of the phagocytic receptors which assists the elimination of synapses by astrocytes. Here, we investigated how ß-amyloid peptide 1-42 (Aß1-42), Iso and Xe interact with MEGF10-dependent synapse elimination. Murine cultured astrocytes as well as cortical and hippocampal ex vivo brain slices were treated with either Aß1-42, Iso or Xe and the combination of Aß1-42 with either Iso or Xe. We quantified MEGF10 expression in astrocytes and dendritic spine density (DSD) in slices. In brain slices of wild type and AAV-induced MEGF10 knock-down mice, antibodies against astrocytes (GFAP), pre- (synaptophysin) and postsynaptic (PSD95) components were used for co-localization analyses by means of immunofluorescence-imaging and 3D rendering techniques. Aß1-42 elevated pre- and postsynaptic components inside astrocytes and decreased DSD. The combined application with either Iso or Xe reversed these effects. In the presence of Aß1-42 both anaesthetics decreased MEGF10 expression. AAV-induced knock-down of MEGF10 reduced the pre- and postsynaptic marker inside astrocytes. The presented data suggest Iso and Xe are able to reverse the Aß1-42-induced enhancement of synaptic elimination in ex vivo hippocampal brain slices, presumably through MEGF10 downregulation.

Acute-stress induces the structural plasticity in hippocampal neurons of 15 and 30-day-old chick, Gallus gallus domesticus.

To study the stress effect on neuronal architecture in the avian hippocampus (a vital component of the neural circuitry mediating stress responses), chick constitutes an interesting animal model. The hippocampus due to its susceptible and vulnerable nature towards acute-stress effect shows pronounced structural and morphological plasticity. Therefore, to perform a detailed investigation of the acute-stress effect on neuronal architecture in the hippocampus, the present study targets to examine the role of a single acute-stress session of 24-hours food and water deprivation in inducing structural plasticity in 15 and 30-day-old chick by using Golgi-Cox staining technique.The findings of the present study have displayed that the chick hippocampus contains highly spinous multipolar, pyramidal, and stellate neuronal cells, along with four variably shaped spines namely filopodia, thin, stubby, and mushroom, over their dendritic branches. In the hippocampus of a 15-day-old chick, the multipolar projection and the stellate neurons show a significant decrease in their spine density under acute-stress, while the pyramidal projection neurons show a significant increase. All the hippocampus neuronal cells of 30-day-old chicks have shown a significant decrease in their dendritic spine density under stressful environment. Therefore, the present research study establishes structural plasticity in hippocampus neurons due to changes in environmental conditions that may affect the animal's behavior.