Cognitive Defects Research Articles

Z-Guggulsterone attenuates cognitive defects and decreases neuroinflammation in APPswe/PS1dE9 mice through inhibiting the TLR4 signaling pathway

Growing evidence indicates that inflammatory damage is implicated in the pathogenesis of Alzheimer’s disease (AD). Z-Guggulsterone (Z-GS) is a natural steroid, which is extracted from Commiphora mukul and has anti-inflammatory effects in vivo and in vitro. In the present study, we investigated the disease-modifying effects of chronic Z-GS administration on the cognitive and neuropathological impairments in the transgenic mouse models of AD. We found that chronic Z-GS administration prevented learning and memory deficits in the APPswe/PS1dE9 mice. In addition, Z-GS treatment significantly decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that Z-GS treatment markedly alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated TLR4/NF-κB signaling pathways in APPswe/PS1dE9 mice were remarkably inhibited by Z-GS treatment, which was achieved via suppressing the phosphorylation of JNK. Collectively, our data demonstrate that chronic Z-GS treatment restores cognitive defects and reverses multiple neuropathological impairments in the APPswe/PS1dE9 mice. This study provides novel insights into the neuroprotective effects and neurobiological mechanisms of Z-GS on AD, indicating that Z-GS is a promising disease-modifying agent for the treatment of AD.

Morphine Aggravates Inflammatory, Behavioral, and Hippocampal Structural Deficits in Septic Rats

Although pain and sepsis are standard comorbidities of intensive care units, reported data on whether pain control by opioid analgesics could alter inflammatory and end‐organ damage caused by sepsis remain contradictory and inconclusive. Here, we tested the hypothesis that morphine, the gold standard narcotic analgesic, modifies behavioral and hippocampal structural defects induced by sepsis in rats. Sepsis was induced with cecal ligation and puncture (CLP) and behavioral studies were undertaken 24 hr later in septic and/or morphine‐treated animals. The induction of sepsis or exposure to morphine (7 mg/kg) elicited similar: (i) falls in systolic blood pressure, (ii) alterations in spatial memory and learning tested by the Morris water maze (increases in escape latency, and decreases in time spent on quadrant plate, distance travelled, and number of crossings), and (iii) depression of exploratory behavior measured by the new object recognition test. These hemodynamic and cognitive defects were significantly exaggerated in septic rats treated with morphine compared with individual interventions. Similar patterns of amplified inflammatory (IL‐1β) and histopathological signs of hippocampal damage (neuronal degeneration, satellitosis, and neuronophagia) were noted in morphine‐treated septic rats. We also show that the presence of intact opioid receptors is mandatory for the elicitation of behavioral and hemodynamic effects of morphine because no such effects were observed after simultaneous blockade of these receptors by naloxone. Together, these findings suggest that morphine acts probably via opioid receptors to provoke sepsis manifestations of inflammation, and behavioral and hippocampal deficits.

Structure and mechanism of addictive impulsivity based on the interaction between drive and control

<p id="p00005">Impulsivity, consisted of driving forces and controlling forces, is an endophenotypic feature which predicts addiction. The driving force is the factor that determines the impulsivity of addiction, while inhibitory control plays the role of regulating the driving force. The addicts of different types all tend to act at a low level of inhibitory control and an abnormally high level of driving force. The imbalance of the two forces can result in drug abuse and relapse. <br/>Reward effect of substance is the main driving force of addiction. Besides, the stimulus-response association triggered by conditional learning, and the personality traits of addicts such as sensation seeking and negative urgency, are all factors associated with driving force. These psychological phenomena can trigger significant impulsivity and evoke habitual and compulsive drug use when inhibitory control is low. <br/>The controlling force mainly includes: the response inhibition characteristic that related to impulsivity personality trait, the cognitive control defect (waiting impulsivity) that cannot delay gratification. Behavioral and neurophysiological studies showed that addicts do possess the traits of low inhibitory control, including at least high sensation seeking and low response inhibition. Rooted in the unusual neurophysiological mechanism, these characteristics may result in the innate susceptibility to drug use and weak inhibitory control among individuals with addition. Waiting impulsivity based on ventral striatum - prefrontal lobe function may also relate to inherited personality traits. <br/> For individuals with addiction, response inhibition and executive control functions that regulate their impulsivity level are influenced by genetic factors and may deteriorate along the course of drug use. The inhibitory and executive control of addicts cannot regulate the tendency of drug use caused by driving forces, thus resulting in impulsive drug use in different stages of addiction.Empirical studies have found that inhibitory control functions remain largely unchanged after short-term abstinence. Moreover, the psychological phenomenon of impulsive personality, which is hereditary, is difficult to be changed within a short time. That is to say, even after a long-term abstinence, it is hardly possible for addicts to elevate the inhibitory control fundamentally. Therefore, one potential way to decrease impulsivity is to alleviate the driving force. Through reducing the reward effect, eliminating the S-R connection or reducing the appearance of related stimulus, the driving force can be decreased, thereby mitigating the impulsivity of drug use. This method might be effective in the treatment of addiction and the prevention of relapse with strong practicability and applicability.

Upregulation of Hippocampal MAPKERK/NFκB Signaling Accounts for the Opioid Receptor‐dependent Incitement of Cognitive Impairment in Septic Rats

Earlier reports indicate that morphine provokes cognitive and circulatory defects caused by sepsis. Pharmacologic, histopathologic, and molecular studies were employed in this communication to implicate inflammatory pathways of the hippocampus in this clinically relevant sepsis‐morphine interaction. Sepsis was induced with cecal ligation and puncture and behavioral studies were undertaken 24 hr later. The data showed that the subcutaneous treatment of septic rats with morphine (7 mg/kg, 6 and 24 hr prior to sepsis) caused significant (i) decreases in systolic blood pressure measured by the tail‐cuff plethysmography, and (ii) impairment in cognitive function as revealed by Morris water maze test, new object recognition test, and Y maze test. Such hemodynamic and behavioral anomalies were substantially obliterated after blockade of opioid receptors or inhibition of TNFα with naloxone (0.5 mg/kg) and infliximab (6 mg/kg), respectively. The improvement in cognitive function caused by naloxone or infliximab was paralleled with dramatic falls in serum IL‐1β and diminution in neuronal degeneration and necrosis seen in hippocampal tissues. Immunohistochemical studies revealed that the heightened hippocampal expression of MAPKERK and NFκB observed in the sepsis/morphine‐challenged rats was remarkably reduced upon treatment with naloxone or infliximab. These findings incriminate opioid receptors in the amplified hemodynamic and behavioral sequalae of sepsis and suggest a therapeutic potential for the downregulation of hippocampal MAPKERK/NFκB cascade in offsetting the exaggerated responsiveness to the sepsis/morphine insult.

Association among postpartum posttraumatic stress disorder, family coping, neurodevelopment, and language development in high-risk infants: a retrospective study.

BackgroundA high-risk infant (HRI) is a child whose fetal, neonatal, and infant development is impacted by adverse factors that may cause cognitive, sensory, behavioral, or language defects. The complex situation in the treatment process is a continuous challenge and stressor for parents. If parents fail to take appropriate coping styles, it will have an adverse impact on the health of parents and the growth and development of children. The purpose of this study was to explore the impact of clinical characteristics, postpartum posttraumatic stress disorder (PTSD), and family coping on the neurodevelopment and language development of HRIs as a reference for targeted intervention.MethodsThis study retrospectively recruited 211 children who were hospitalized in the neonatal intensive care unit (NICU) of Suzhou Kowloon Hospital from January 2018 to December 2021. HRI and their mother were interviewed by telephone with general information questionnaire, Perinatal Post-traumatic Stress Disorder Questionnaire, medical coping modes questionnaire, Bayley Scales of Infant Development the Early Language Milestone Scale to investigate HRI and their mothers; Logistic regression was used to analyze the relationship between HRI mothers’ emotions and family coping with neurodevelopment and language development.ResultsThe neurodevelopmental scores of HRIs differed according to gestational week of delivery, birth weight, and disease diagnosis. The language development scores of HRIs differed according to gestational week of delivery, birth weight, disease diagnosis, and maternal education. Multiple stepwise regression analysis showed that the neurodevelopmental scores were affected by gestational week of delivery, postpartum PTSD score, and family coping. Logistic regression analysis showed that the language development scores were affected by maternal education and neurodevelopmental level. The correlation analysis showed that the postpartum PTSD scores were negatively correlated with family coping, neurodevelopment, and language development, and that family coping was positively correlated with the neurodevelopment and language development scores (P<0.05).ConclusionsThe neurodevelopment and language development of HRIs were affected by the gestational week of delivery, maternal education, the child’s birth weight, and disease diagnosis. NICU wards can promote the healthy development of HRIs by providing mothers with targeted health education concerning the child’s condition, postpartum PTSD, and family coping strategies.

Posttranslational modification of microtubules by the MATCAP detyrosinase.

The detyrosination-tyrosination cycle involves the removal and religation of the C-terminal tyrosine of α-tubulin and is implicated in cognitive, cardiac, and mitotic defects. The vasohibin-small vasohibin-binding protein (SVBP) complex underlies much, but not all, detyrosination. We used haploid genetic screens to identify an unannotated protein, microtubule associated tyrosine carboxypeptidase (MATCAP), as a remaining detyrosinating enzyme. X-ray crystallography and cryo-electron microscopy structures established MATCAP's cleaving mechanism, substrate specificity, and microtubule recognition. Paradoxically, whereas abrogation of tyrosine religation is lethal in mice, codeletion of MATCAP and SVBP is not. Although viable, defective detyrosination caused microcephaly, associated with proliferative defects during neurogenesis, and abnormal behavior. Thus, MATCAP is a missing component of the detyrosination-tyrosination cycle, revealing the importance of this modification in brain formation.

Enhancing GluN2A-type NMDA receptors impairs long-term synaptic plasticity and learning and memory.

N-methyl-D-aspartic acid type glutamate receptors (NMDARs) play critical roles in synaptic transmission and plasticity, the dysregulation of which leads to cognitive defects. Here, we identified a rare variant in the NMDAR subunit GluN2A (K879R) in a patient with intellectual disability. The K879R mutation enhanced receptor expression on the cell surface by disrupting a KKK motif that we demonstrated to be an endoplasmic reticulum retention signal. Expression of GluN2A_K879R in mouse hippocampal CA1 neurons enhanced the excitatory postsynaptic currents mediated by GluN2A-NMDAR but suppressed those mediated by GluN2B-NMDAR and the AMPA receptor. GluN2A_K879R knock-in mice showed similar defects in synaptic transmission and exhibited impaired learning and memory. Furthermore, both LTP and LTD were severely impaired in the KI mice, likely explaining their learning and memory defects. Therefore, our study reveals a new mechanism by which elevated synaptic GluN2A-NMDAR impairs long-term synaptic plasticity as well as learning and memory.

Iron Chelation Remits Memory Deficits Caused by the High-Fat Diet in a Mouse Model of Alzheimer's Disease.

Obesity is a worldwide health problem that has been implicated in many diseases, including Alzheimer's disease (AD). AD is one of the most common neurodegenerative disorders and is characterized by two pathologies, including extracellular senior plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) consisting of abnormally hyperphosphorylated tau. According to current research, a high-fat diet (HFD) could exacerbate Aβ accumulation, oxidative damage, and cognitive defects in AD mice. However, the accurate role of HFD in the pathogenesis of AD is far more unclear. To explore the accurate role of HFD in the pathogenesis of AD. Open Field, Barns Maze, Elevated zero-maze, Contextual fear condition, Tail suspension test, western blotting, immunofluorescence, Fluoro-Jade C Labeling, Perls' Prussian blue staining, and ELISA were used. HFD caused nonheme iron overload in the brains of APPswe/PS1dE9 (APP/PS1) mice. Furthermore, the administration of M30 (0.5 mg/kg) for iron chelation once every 2 days per os (p.o.) for 1 month remitted memory deficits caused by HFD in APP/PS1 mice. Notably, a variety of hematological parameters in whole blood had no difference after iron chelation. In addition, iron chelation effectively reduced synaptic impairment in hippocampus and neuronal degeneration in cortex in the HFD-fed APP/PS1 mice. Meanwhile, iron chelation decreased Aβ1-40 and Aβ1-42 level as well as neuroinflammation in HFD-fed APP/PS1 mice. These data enhance our understanding of how HFD aggravates AD pathology and cognitive impairments and might shed light on future preclinical studies.

Early-onset Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of cognitive impairment in adults. There are two main forms of AD: early-onset (onset before 65 years) and late-onset (onset after 65 years). Early-onset AD accounts for at least 5% of all disease cases. The risk of early-onset AD increases in the presence of a family burden and a history of traumatic brain injury. However, it is less associated with cerebrovascular disease, diabetes mellitus, and obesity compared to late-onset AD. The article provides a review of current publications on the diagnostic and treatment problems in early forms of AD. Clinical, neuropsychological and neuroimaging differences between AD with early and late onset are presented.On the example of a clinical observation of a patient with AD with an onset at the age of 38 years, stabilization of the cognitive defect for 6 months and a decrease in the severity of emotional and behavioral disorders after Akatinol Memantine administration are shown. The main problems of management of young patients with AD are considered.

The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer’s disease

The development of new therapeutic avenues that target the early stages of Alzheimer's disease (AD) is urgently necessary. A disintegrin and metalloproteinase domain 10 (ADAM10) is a sheddase that is involved in dendritic spine shaping and limits the generation of amyloid-β. ADAM10 endocytosis increases in the hippocampus of AD patients, resulting in the decreased postsynaptic localization of the enzyme. To restore this altered pathway, we developed a cell-permeable peptide (PEP3) with a strong safety profile that is able to interfere with ADAM10 endocytosis, upregulating the postsynaptic localization and activity of ADAM10. After extensive validation, experiments in a relevant animal model clarified the optimal timing of the treatment window. PEP3 administration was effective for the rescue of cognitive defects in APP/PS1 mice only if administered at an early disease stage. Increased ADAM10 activity promoted synaptic plasticity, as revealed by changes in the molecular compositions of synapses and the spine morphology. Even though further studies are required to evaluate efficacy and safety issues of long-term administration of PEP3, these results provide preclinical evidence to support the therapeutic potential of PEP3 in AD.

Sacubitril-Valsartan And 5-Year Incidence Of Neurocognitive Diagnoses

Introduction Sacubitril inhibits neprilysin in the kidneys, preventing degradation of natriuretic peptides, thus augmenting natriuresis and vasodilation. However, neprilysin is also expressed in the central nervous system and is involved in the degradation of beta amyloid, which has been associated with Alzheimer's disease (AD) and other cognitive defects. Experimental studies with sacubitril/valsartan (S/V) have fueled theoretical concerns about neurocognitive side effects, but clinical data are scarce. Hypothesis We hypothesized that 5-year incidence of new neurocognitive diagnoses (AD, dementia, and cognitive decline) among patients with HF who have switched to S/V does not differ from that of patients with HF receiving an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) alone. Methods Using data from the TriNetX electronic health records network, we examined relevant neurological outcomes in (1) an S/V cohort, comprising of adults (age ≥18) with systolic HF (ICD-10 I50.2) who were switched from ACEi or ARB to S/V between 2015 and 2019 (to allow for ≥1 year of followup) and (2) a propensity-matched (for over 100 clinical characteristics) cohort of adults with systolic HF who were receiving exclusively ACEI or ARB during the same period (to eliminate temporal bias). We evaluated for new: (1) AD (ICD-10: G30); (2) dementia (ICD-10: F01-F03); and (3) any cognitive decline (ICD-10: R41.8). We used Cox proportional hazards models to compare incidence between matched cohorts. Results The baseline characteristics of the matched cohorts (N=19,553 for each cohort) were well balanced (Table 1); all standardized mean differences were <0.1, indicating adequate matching. Kaplan-Meier mortality at 5 years was 25.8% in S/V vs. 31.2% in ACEi/ARB (log-rank P<0.001). After excluding patients with prevalent diagnoses of interest at baseline, the incidences of AD, dementia, and cognitive decline were all lower in the S/V group (Table 2). Conclusions Despite theoretical concerns, the incidence of neurocognitive diagnoses was lower among S/V recipients in this large-cohort, propensity-matched analysis of systolic HF patients. Whether S/V is beneficial in this aspect needs prospective evaluation. Sacubitril inhibits neprilysin in the kidneys, preventing degradation of natriuretic peptides, thus augmenting natriuresis and vasodilation. However, neprilysin is also expressed in the central nervous system and is involved in the degradation of beta amyloid, which has been associated with Alzheimer's disease (AD) and other cognitive defects. Experimental studies with sacubitril/valsartan (S/V) have fueled theoretical concerns about neurocognitive side effects, but clinical data are scarce. We hypothesized that 5-year incidence of new neurocognitive diagnoses (AD, dementia, and cognitive decline) among patients with HF who have switched to S/V does not differ from that of patients with HF receiving an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) alone. Using data from the TriNetX electronic health records network, we examined relevant neurological outcomes in (1) an S/V cohort, comprising of adults (age ≥18) with systolic HF (ICD-10 I50.2) who were switched from ACEi or ARB to S/V between 2015 and 2019 (to allow for ≥1 year of followup) and (2) a propensity-matched (for over 100 clinical characteristics) cohort of adults with systolic HF who were receiving exclusively ACEI or ARB during the same period (to eliminate temporal bias). We evaluated for new: (1) AD (ICD-10: G30); (2) dementia (ICD-10: F01-F03); and (3) any cognitive decline (ICD-10: R41.8). We used Cox proportional hazards models to compare incidence between matched cohorts. The baseline characteristics of the matched cohorts (N=19,553 for each cohort) were well balanced (Table 1); all standardized mean differences were <0.1, indicating adequate matching. Kaplan-Meier mortality at 5 years was 25.8% in S/V vs. 31.2% in ACEi/ARB (log-rank P<0.001). After excluding patients with prevalent diagnoses of interest at baseline, the incidences of AD, dementia, and cognitive decline were all lower in the S/V group (Table 2). Despite theoretical concerns, the incidence of neurocognitive diagnoses was lower among S/V recipients in this large-cohort, propensity-matched analysis of systolic HF patients. Whether S/V is beneficial in this aspect needs prospective evaluation.

Dopey proteins are essential but overlooked regulators of membrane trafficking.

Dopey family proteins play crucial roles in diverse processes from morphogenesis to neural function and are conserved from yeast to mammals. Understanding the mechanisms behind these critical functions could have major clinical significance, as dysregulation of Dopey proteins has been linked to the cognitive defects in Down syndrome, as well as neurological diseases. Dopey proteins form a complex with the non-essential GEF-like protein Mon2 and an essential lipid flippase from the P4-ATPase family. Different combinations of Dopey, Mon2 and flippases have been linked to regulating membrane remodeling, from endosomal recycling to extracellular vesicle formation, through their interactions with lipids and other membrane trafficking regulators, such as ARL1, SNX3 and the kinesin-1 light chain KLC2. Despite these important functions and their likely clinical significance, Dopey proteins remain understudied and their roles elusive. Here, we review the major scientific discoveries relating to Dopey proteins and detail key open questions regarding their function to draw attention to these fascinating enigmas.

A Brief Notes on Gene Therapy, Cell Therapy and Cell-Based Gene Therapy for Alzheimer’s Disease

Alzheimer’s disease (AD) is known as an age-related neurodegenerative disease where progressive loss of memory associated with cognition defects has been noticed. Molecular analysis of AD revealed the formation of aggregated amyloid-β protein and hyper phosphorylated tau tangles at the synaptic circuit, which causes the loss of neuronal communication.

Deferoxamine ameliorated Al(mal)3-induced neuronal ferroptosis in adult rats by chelating brain iron to attenuate oxidative damage

Aluminum (Al), a neurotoxic element, can induce Alzheimer’s disease-like (AD-like) changes by triggering neuronal death. Iron homeostasis disturbance has also been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of neuronal death induced by aluminum maltolate (Al(mal)3) in the pathogenesis of AD remains elusive. In this study, the results of three different behavioral experiments suggested that the learning and memory ability deteriorated and autonomous activity declined of these rats that exposed Al(mal)3 were alleviated by deferoxamine (DFO). Transmission electron microscope observations showed that the membrane was ruptured, and the membrane density increased and ridge disappearance (the most prominent characteristic of ferroptosis) in the perinuclear and cytoplasmic compartments of the hippocampal neurons were perceived in the exposure group, while the DFO group and 18 μM/kg Al(mal)3+DFO group were alleviated compared with 18 μM/kg Al(mal)3. In addition, DFO prevented oxidative stress, such as increased glutathione (GSH) and decreased malondialdehyde (MDA) and reactive oxygen species (ROS), while the latter two indexes had the same changing tendency as the total iron of brain tissue. These data indicated that Al(mal)3 could cause ferroptosis in Sprague-Dawley (SD) rat neurons, which was inhibited by DFO via reducing the content of iron and increasing the ability of cells to resist oxidative damage.

Dysregulation of miRNAs Levels in Glycogen Synthase Kinase-3β Overexpressing Mice and the Role of miR-221-5p in Synaptic Function

Glycogen synthase kinase-3β (GSK-3β) is a highly expressed kinase in the brain, where it has an important role in synaptic plasticity. Aberrant activity of GSK-3β leads to synaptic dysfunction which results in the development of several neuropsychiatric and neurological diseases. Notably, overexpression of constitutively active form of GSK-3β (GSK-3β[S9A]) in mice recapitulates the cognitive and structural defects characteristic for neurological and psychiatric disorders. However, the mechanisms by which GSK-3β regulates synaptic functions are not clearly known. Here, we investigate the effects of GSK-3β overactivity on neuronal miRNA expression in the mouse hippocampus. We found that GSK-3β overactivity downregulates miRNA network with a potent effect on miR-221-5p (miR-221*). Next, characterization of miR-221* function in primary hippocampal cell culture transfected by miR-221* inhibitor, showed no structural changes in dendritic spine shape and density. Using electrophysiological methods, we found that downregulation of miR-221* increases excitatory synaptic transmission in hippocampal neurons, probably via postsynaptic mechanisms. Thus, our data reveal potential mechanism by which GSK-3β and miRNAs might regulate synaptic function and therefore also synaptic plasticity.

Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.

Preventive putative mechanisms involved in the psychopathologies of mice passively coping with psychosocial defeat stress by quercetin

Derangements of neuroimmune, neurotrophic and neurochemical homeostasis have important implications in psychosocial stress-induced psychopathologies. Whether quercetin, a neuroactive compound, protects against psychosocial stress-induced psychiatric disturbances particularly via neurochemical mechanisms remain less well elucidated. Therefore, we further investigated the putative neurochemical as well as other cellular mechanisms of quercetin on social-defeat stress (SDS) model of psychosocial impairments. Saline (10 mL/kg,i.p.), quercetin (25, 50 and 100 mg/kg,i.p.) and ginseng (50 mg/kg,i.p.) were given to intruder mice for 14 days. From days 7–14, ten minutes of aggressive-resident-induced SDS (physical and psychological) were conducted thirty minutes after treatments. Subsequently, behavioral assessments: open-field, light/dark board, Y-maze, novel-object recognition, social-interaction and tail-suspension tests were conducted on day 14. Adrenal weight and glucose levels were measured. Monoamines, brain-derived neurotrophic factor (BDNF), corticosterone, inflammatory cytokines (TNF-α, IL-6) and executioner caspase-3 concentrations were determined in specific brain regions by ELISA. Oxidative/nitrergic stress and cholinergic markers were determined with UV-spectrophotometry. Psychosocial stress-induced anxiety, depression and cognitive defects were improved by quercetin. The decreased serotonin in the prefrontal-cortex and dopamine in the striatum, elevated levels of noradrenaline and acetylcholinesterase in the prefrontal-cortex and hippocampus with corresponding decrease in BDNF were reversed by quercetin. Quercetin reduced SDS-induced increased neuronal inflammation, caspase-3 activity, malondialdehyde, nitrite levels, but increased antioxidant activities in the three brain regions. Adrenal hypertrophy, increased serum glucose and corticosterone release were reduced by quercetin. Our findings showed that quercetin attenuates psychosocial stress-induced passive coping behavior via normalization of HPA-axis, modulation of neurochemical release, enhancement of BDNF, and inhibition of brain oxidative/nitrergic stress, neuroinflammation and apoptotic pathway.

Aberrant hippocampal transmission and behavior in mice with a stargazin mutation linked to intellectual disability

Mutations linked to neurodevelopmental disorders, such as intellectual disability (ID), are frequently found in genes that encode for proteins of the excitatory synapse. Transmembrane AMPA receptor regulatory proteins (TARPs) are AMPA receptor auxiliary proteins that regulate crucial aspects of receptor function. Here, we investigate a mutant form of the TARP family member stargazin, described in an ID patient. Molecular dynamics analyses predicted that the ID-associated stargazin variant, V143L, weakens the overall interface of the AMPAR:stargazin complex and impairs the stability of the complex. Knock-in mice harboring the V143L stargazin mutation manifest cognitive and social deficits and hippocampal synaptic transmission defects, resembling phenotypes displayed by ID patients. In the hippocampus of stargazin V143L mice, CA1 neurons show impaired spine maturation, abnormal synaptic transmission and long-term potentiation specifically in basal dendrites, and synaptic ultrastructural alterations. These data suggest a causal role for mutated stargazin in the pathogenesis of ID and unveil a new role for stargazin in the development and function of hippocampal synapses.

EP197: Further delineation of KIF21B-related neurodevelopmental disorders

KIF21B (Kinesin Family Member 21B) encoded by KIF21B (MIM*608322), belongs to the Kinesin Superfamily proteins, which play a key role in microtubular organisation in neuronal dendrites and axons. KIF21B regulates microtubule network dynamics and promotes intracellular anterograde transport in neurons. Homozygous knock out mice were shown to have microcephaly, altered synaptic transmission, cognitive defects and reduced dendritic complexity, implicating the role of KIF21B in brain function. Recently, four unrelated individuals with developmental delay, intellectual disability, nonspecific facial dysmorphism and corpus callosal agenesis were described with heterozygous variants in KIF21B.

Loss of central mineralocorticoid or glucocorticoid receptors impacts auditory nerve processing in the cochlea

SummaryThe key auditory signature that may associate peripheral hearing with central auditory cognitive defects remains elusive. Suggesting the involvement of stress receptors, we here deleted the mineralocorticoid and glucocorticoid receptors (MR and GR) using a CaMKIIα-based tamoxifen-inducible CreERT2/loxP approach to generate mice with single or double deletion of central but not cochlear MR and GR. Hearing thresholds of MRGRCaMKIIαCreERT2 conditional knockouts (cKO) were unchanged, whereas auditory nerve fiber (ANF) responses were larger and faster and auditory steady state responses were improved. Subsequent analysis of single MR or GR cKO revealed discrete roles for both, central MR and GR on cochlear functions. Limbic MR deletion reduced inner hair cell (IHC) ribbon numbers and ANF responses. In contrast, GR deletion shortened the latency and improved the synchronization to amplitude-modulated tones without affecting IHC ribbon numbers. These findings imply that stress hormone-dependent functions of central MR/GR contribute to “precognitive” sound processing in the cochlea.