Abatacept inhibits Th17 differentiation and mitigates α-synuclein-induced dopaminergic dysfunction in mice.

Parkinson's disease (PD) is a multifaceted disease characterized by degeneration of nigrostriatal dopaminergic neurons, which results in motor and non-motor dysfunctions. Accumulation of α-synuclein (αSYN) in Lewy bodies is a key pathological feature of PD. Although the exact cause of PD remains unknown, accumulating evidence suggests that brain infiltration of T cells plays a critical role in the pathogenesis of disease, contributing to neuroinflammation and dopaminergic neurodegeneration. Here, we used a mouse model of brain-infused aggregated αSYN, which recapitulates motor and non-motor dysfunctions seen in PD patients. We found that αSYN-induced motor dysfunction in mice is accompanied by an increased number of brain-residing Th17 (IL17+ CD4+) cells, but not CD8+ T cells. To evaluate whether the modulation of T cell response could rescue αSYN-induced damage, we chronically treated animals with abatacept (8 mg/kg, sc, 3x per week), a selective T-cell co-stimulation modulator. We found that abatacept treatment decreased Th1 (IFNƔ+ CD4+) and Th17 (IL17+ CD4+) cells in the brain, rescued motor function and prevented dopaminergic neuronal loss in αSYN-infused mice. These results highlight the significance of effector CD4+ T cells, especially Th17, in the progression of PD and introduce novel possibilities for repurposing immunomodulatory drugs used for arthritis as PD-modifying therapies.

Fundamental neurochemistry review: Glutamatergic dysfunction as a central mechanism underlying flavivirus-induced neurological damage.

The Flaviviridae family comprises positive-sense single-strand RNA viruses mainly transmitted by arthropods. Many of these pathogens are especially deleterious to the nervous system, and a myriad of neurological symptoms have been associated with infections by Zika virus (ZIKV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) in humans. Studies suggest that viral replication in neural cells and the massive release of pro-inflammatory mediators lead to morphological alterations of synaptic spine structure and changes in the balance of excitatory/inhibitory neurotransmitters and receptors. Glutamate is the predominant excitatory neurotransmitter in the brain, and studies propose that either enhanced release or impaired uptake of this amino acid contributes to brain damage in several conditions. Here, we review existing evidence suggesting that glutamatergic dysfunction-induced by flaviviruses is a central mechanism for neurological damage and clinical outcomes of infection. We also discuss current data suggesting that pharmacological approaches that counteract glutamatergic dysfunction show benefits in animal models of such viral diseases.

Mice lacking 5-lipoxygenase display motor deficits associated with cortical and hippocampal synapse abnormalities.

Neural-immune interactions are related to the synapse plasticity and other dynamic processes in the nervous system. The absence or dysfunction of cellular/molecular elements from the immune system lead to impairments in the central and peripheral nervous system with behavior consequences such as cognitive, sensory, and locomotor deficits as well as social disabilities and anxiety disturbances. Cellular interactions between immune cells such as macrophages, microglia, and neutrophils with glial or neuronal cells have been of increasing interest over the last years. However, little is known about the role of immune-derived soluble factors in the context of homeostasis of the nervous system. Leukotrienes (LTs) are lipid mediators derived from the oxidation of arachidonic acid by 5-lipoxygenase (5-LO), and are classically involved in inflammation, allergies, and asthma. Here, we demonstrated that adult mice lacking 5-LO (5-LO-/-) showed motor deficits in rotarod test and increased repetitive behavior (marble burying test). These behavioral changes are accompanied by increased levels of synapse proteins (PSD95 and synaptophysin) at the motor cortex and hippocampus, but not with BDNF alterations. No changes in microglial cell density or morphology were seen in the brains of 5-LO-/- mice. Furthermore, expression of fractalkine receptor CX3CR1 was increased and of its ligand CX3CL1 was decreased in the cortex of 5-LO-/- mice. Here we provide evidence for the involvement of 5-LO products structuring synapses network with motor behavior consequences. We suggest that the absence of 5-LO products lead to modified microglial/neuron interaction, reducing microglial pruning.

Lifelong Exposure to a Low-Dose of the Glyphosate-Based Herbicide RoundUp® Causes Intestinal Damage, Gut Dysbiosis, and Behavioral Changes in Mice.

RoundUp® (RUp) is a comercial formulation containing glyphosate (N-(phosphono-methyl) glycine), and is the world's leading wide-spectrum herbicide used in agriculture. Supporters of the broad use of glyphosate-based herbicides (GBH) claim they are innocuous to humans, since the active compound acts on the inhibition of enzymes which are absent in human cells. However, the neurotoxic effects of GBH have already been shown in many animal models. Further, these formulations were shown to disrupt the microbiome of different species. Here, we investigated the effects of a lifelong exposure to low doses of the GBH-RUp on the gut environment, including morphological and microbiome changes. We also aimed to determine whether exposure to GBH-RUp could harm the developing brain and lead to behavioral changes in adult mice. To this end, animals were exposed to GBH-RUp in drinking water from pregnancy to adulthood. GBH-RUp-exposed mice had no changes in cognitive function, but developed impaired social behavior and increased repetitive behavior. GBH-Rup-exposed mice also showed an activation of phagocytic cells (Iba-1-positive) in the cortical brain tissue. GBH-RUp exposure caused increased mucus production and the infiltration of plama cells (CD138-positive), with a reduction in phagocytic cells. Long-term exposure to GBH-RUp also induced changes in intestinal integrity, as demonstrated by the altered expression of tight junction effector proteins (ZO-1 and ZO-2) and a change in the distribution of syndecan-1 proteoglycan. The herbicide also led to changes in the gut microbiome composition, which is also crucial for the establishment of the intestinal barrier. Altogether, our findings suggest that long-term GBH-RUp exposure leads to morphological and functional changes in the gut, which correlate with behavioral changes that are similar to those observed in patients with neurodevelopmental disorders.

Innate immune memory mediates increased susceptibility to Alzheimer's disease-like pathology in sepsis surviving mice.

Sepsis survivors show long-term impairments, including alterations in memory and executive function. Evidence suggests that systemic inflammation contributes to the progression of Alzheimers disease (AD), but the mechanisms involved in this process are still unclear. Boosted (trained) and diminished (tolerant) innate immune memory has been described in peripheral immune cells after sepsis. However, the occurrence of long-term innate immune memory in the post-septic brain is fully unexplored. Here, we demonstrate that sepsis causes long-lasting trained innate immune memory in the mouse brain, leading to an increased susceptibility to Aß oligomers (AßO), central neurotoxins found in AD. Hippocampal microglia from sepsis-surviving mice shift to an amoeboid/phagocytic morphological profile when exposed to low amounts of AßO, and this event was accompanied by the upregulation of several pro-inflammatory proteins (IL-1ß, IL-6, INF-γ and P2X7 receptor) in the mouse hippocampus, suggesting that a trained innate immune memory occurs in the brain after sepsis. Brain exposure to low amounts of AßO increased microglial phagocytic ability against hippocampal synapses. Pharmacological blockage of brain phagocytic cells or microglial depletion, using minocycline and colony stimulating factor 1 receptor inhibitor (PLX3397), respectively, prevents cognitive dysfunction induced by AßO in sepsis-surviving mice. Altogether, our findings suggest that sepsis induces a long-lasting trained innate immune memory in the mouse brain, leading to an increased susceptibility to AßO-induced neurotoxicity and cognitive impairment.

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD-linked amyloid-ß oligomers (AßOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AßOs into the lateral cerebral ventricle of non-human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD-related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP-1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Interaction of amyloid-ß (Aß) oligomers with neurexin 2α and neuroligin 1 mediates synapse damage and memory loss in mice.

Brain accumulation of the amyloid-ß protein (Aß) and synapse loss are neuropathological hallmarks of Alzheimer disease (AD). Aß oligomers (AßOs) are synaptotoxins that build up in the brains of patients and are thought to contribute to memory impairment in AD. Thus, identification of novel synaptic components that are targeted by AßOs may contribute to the elucidation of disease-relevant mechanisms. Trans-synaptic interactions between neurexins (Nrxs) and neuroligins (NLs) are essential for synapse structure, stability, and function, and reduced NL levels have been associated recently with AD. Here we investigated whether the interaction of AßOs with Nrxs or NLs mediates synapse damage and cognitive impairment in AD models. We found that AßOs interact with different isoforms of Nrx and NL, including Nrx2α and NL1. Anti-Nrx2α and anti-NL1 antibodies reduced AßO binding to hippocampal neurons and prevented AßO-induced neuronal oxidative stress and synapse loss. Anti-Nrx2α and anti-NL1 antibodies further blocked memory impairment induced by AßOs in mice. The results indicate that Nrx2α and NL1 are targets of AßOs and that prevention of this interaction reduces the deleterious impact of AßOs on synapses and cognition. Identification of Nrx2α and NL1 as synaptic components that interact with AßOs may pave the way for development of novel approaches aimed at halting synapse failure and cognitive loss in AD.

Consequences of gestational diabetes to the brain and behavior of the offspring.

Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during the second/third trimesters of pregnancy in previously normoglycemic women. It is currently estimated that 10% of all pregnancies in the United States show this condition. For many years, the transient nature of GD has led researchers and physicians to assume that long-term consequences were absent. However, GD diagnosis leads to a six-fold increase in the risk of developing type 2 diabetes (T2D) in women and incidence of obesity and T2D is also higher among their infants. Recent and concerning evidences point to detrimental effects of GD on the behavior and cognition of the offspring, which often persist until adolescence or adulthood. Considering that the perinatal period is critical for determination of adult behavior, it is expected that the intra-uterine exposure to hyperglycemia, hyperinsulinemia and pro-inflammatory mediators, hallmark features of GD, might affect brain development. Here, we review early clinical and experimental evidence linking GD to consequences on the behavior of the offspring, focusing on memory and mood disorders. We also discuss initial evidence suggesting that downregulation of insulin signaling cascades are seen in the brains of GD offspring and could contribute to the consequences on their behavior.

Chronic sleep restriction promotes brain inflammation and synapse loss, and potentiates memory impairment induced by amyloid-ß oligomers in mice.

It is increasingly recognized that sleep disturbances and Alzheimer's disease (AD) share a bidirectional relationship. AD patients exhibit sleep problems and alterations in the regulation of circadian rhythms; conversely, poor quality of sleep increases the risk of development of AD. The aim of the current study was to determine whether chronic sleep restriction potentiates the brain impact of amyloid-ß oligomers (AßOs), toxins that build up in AD brains and are thought to underlie synapse damage and memory impairment. We further investigated whether alterations in levels of pro-inflammatory mediators could play a role in memory impairment in sleep-restricted mice. We found that a single intracerebroventricular (i.c.v.) infusion of AßOs disturbed sleep pattern in mice. Conversely, chronically sleep-restricted mice exhibited higher brain expression of pro-inflammatory mediators, reductions in levels of pre- and post-synaptic marker proteins, and exhibited increased susceptibility to the impact of i.c.v. infusion of a sub-toxic dose of AßOs (1pmol) on performance in the novel object recognition memory task. Sleep-restricted mice further exhibited an increase in brain TNF-α levels in response to AßOs. Interestingly, memory impairment in sleep-restricted AßO-infused mice was prevented by treatment with the TNF-α neutralizing monoclonal antibody, infliximab. Results substantiate the notion of a dual relationship between sleep and AD, whereby AßOs disrupt sleep/wake patterns and chronic sleep restriction increases brain vulnerability to AßOs, and point to a key role of brain inflammation in increased susceptibility to AßOs in sleep-restricted mice.

Memantine rescues transient cognitive impairment caused by high-molecular-weight aß oligomers but not the persistent impairment induced by low-molecular-weight oligomers.

Brain accumulation of soluble amyloid-ß oligomers (AßOs) has been implicated in synapse failure and cognitive impairment in Alzheimer's disease (AD). However, whether and how oligomers of different sizes induce synapse dysfunction is a matter of controversy. Here, we report that low-molecular-weight (LMW) and high-molecular-weight (HMW) Aß oligomers differentially impact synapses and memory. A single intracerebroventricular injection of LMW AßOs (10 pmol) induced rapid and persistent cognitive impairment in mice. On the other hand, memory deficit induced by HMW AßOs (10 pmol) was found to be reversible. While memory impairment in LMW oligomer-injected mice was associated with decreased hippocampal synaptophysin and GluN2B immunoreactivities, synaptic pathology was not detected in the hippocampi of HMW oligomer-injected mice. On the other hand, HMW oligomers, but not LMW oligomers, induced oxidative stress in hippocampal neurons. Memantine rescued both neuronal oxidative stress and the transient memory impairment caused by HMW oligomers, but did not prevent the persistent cognitive deficit induced by LMW oligomers. Results establish that different Aß oligomer assemblies act in an orchestrated manner, inducing different pathologies and leading to synapse dysfunction. Furthermore, results suggest a mechanistic explanation for the limited efficacy of memantine in preventing memory loss in AD.

Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer's disease.

A link between Alzheimer's disease (AD) and metabolic disorders has been established, with patients with type 2 diabetes at increased risk of developing AD and vice versa. The incidence of metabolic disorders, including insulin resistance and type 2 diabetes is increasing at alarming rates worldwide, primarily as a result of poor lifestyle habits. In parallel, as the world population ages, the prevalence of AD, the most common form of dementia in the elderly, also increases. In addition to their epidemiologic and clinical association, mounting recent evidence indicates shared mechanisms of pathogenesis between metabolic disorders and AD. We discuss the concept that peripheral and central nervous system inflammation link the pathogenesis of AD and metabolic diseases. We also explore the contribution of brain inflammation to defective insulin signaling and neuronal dysfunction. Last, we review recent evidence indicating that targeting neuroinflammation may provide novel therapeutic avenues for AD.

TNF-α blockage prevents late neurological consequences of Zika virus infection in mice.

Zika virus (ZIKV) is a neurotropic Orthoflavivirus that causes a myriad of neurological manifestations in newborns exposed in uterus. Despite the devastating consequences of ZIKV on the developing brain, strategies to prevent or treat the consequences of viral infection are not yet available. We previously showed that short-term treatment with the TNF-α neutralizing monoclonal antibody. Infliximab could prevent seizures at acute and chronic stages of ZIKV infection, but had no impact on long-term cognitive and motor dysfunction. Due to the central role of inflammation in ZIKV-neuropathology, we hypothesized that prolonged treatment with the anti-TNF-α monoclonal antibody Infliximab could provide complete rescue of long-term behavioral deficits associated with neonatal ZIKV infection in mice. Here, neonatal (post-natal day 3) Swiss mice were submitted to subcutaneous (s.c.) injection of 106 PFU of ZIKV or mock medium and were then treated with Infliximab (20 µg/day) or sterile saline intraperitoneally (i.p.), for 40 days starting on the day of infection, and behavioral assessment started at 60 days post-infection (dpi). Infliximab prevented ZIKV-induced cognitive and motor impairments in mice. In addition, microgliosis and cell death found in mice following ZIKV infection were partially reversed by TNF-α blockage. Altogether, these results suggest that TNF-α-mediated inflammation is central for late ZIKV-induced behavioral deficits and cell death and strategies targeting this cytokine may be promising approaches to treat subjects exposed to the virus during development.

Immunosuppression-induced Zika virus reactivation causes brain inflammation and behavioral deficits in mice.

Zika virus (ZIKV) is a neurotropic flavivirus that can persist in several tissues. The late consequences of ZIKV persistence and whether new rounds of active replication can occur, remain unaddressed. Here, we investigated whether neonatally ZIKV-infected mice are susceptible to viral reactivation in adulthood. We found that when ZIKV-infected mice are treated with immunosuppressant drugs, they present increased susceptibility to chemically induced seizures. Levels of subgenomic flavivirus RNAs (sfRNAs) were increased, relative to the amounts of genomic RNAs, in the brains of mice following immunosuppression and were associated with changes in cytokine expression. We investigated the impact of immunosuppression on the testicles and found that ZIKV genomic RNA levels are increased in mice following immunosuppression, which also caused significant testicular damage. These findings suggest that ZIKV can establish new rounds of active replication long after acute stages of disease, so exposed patients should be monitored to ensure complete viral eradication.

Zika virus infection impairs synaptogenesis, induces neuroinflammation, and could be an environmental risk factor for autism spectrum disorder outcome.

Zika virus (ZIKV) infection was first associated with Central Nervous System (CNS) infections in Brazil in 2015, correlated with an increased number of newborns with microcephaly, which ended up characterizing the Congenital Zika Syndrome (CZS). Here, we investigated the impact of ZIKV infection on the functionality of iPSC-derived astrocytes. Besides, we extrapolated our findings to a Brazilian cohort of 136 CZS children and validated our results using a mouse model. Interestingly, ZIKV infection in neuroprogenitor cells compromises cell migration and causes apoptosis but does not interfere in astrocyte generation. Moreover, infected astrocytes lost their ability to uptake glutamate while expressing more glutamate transporters and secreted higher levels of IL-6. Besides, infected astrocytes secreted factors that impaired neuronal synaptogenesis. Since these biological endophenotypes were already related to Autism Spectrum Disorder (ASD), we extrapolated these results to a cohort of children, now 6-7 years old, and found seven children with ASD diagnosis (5.14 %). Additionally, mice infected by ZIKV revealed autistic-like behaviors, with a significant increase of IL-6 mRNA levels in the brain. Considering these evidence, we inferred that ZIKV infection during pregnancy might lead to synaptogenesis impairment and neuroinflammation, which could increase the risk for ASD.

Nanosystems for gene therapy targeting brain damage caused by viral infections.

Several human pathogens can cause long-lasting neurological damage. Despite the increasing clinical knowledge about these conditions, most still lack efficient therapeutic interventions. Gene therapy (GT) approaches comprise strategies to modify or adjust the expression or function of a gene, thus providing therapy for human diseases. Since recombinant nucleic acids used in GT have physicochemical limitations and can fail to reach the desired tissue, viral and non-viral vectors are applied to mediate gene delivery. Although viral vectors are associated to high levels of transfection, non-viral vectors are safer and have been further explored. Different types of nanosystems consisting of lipids, polymeric and inorganic materials are applied as non-viral vectors. In this review, we discuss potential targets for GT intervention in order to prevent neurological damage associated to infectious diseases as well as the role of nanosized non-viral vectors as agents to help the selective delivery of these gene-modifying molecules. Application of non-viral vectors for delivery of GT effectors comprise a promising alternative to treat brain inflammation induced by viral infections.

Different outcomes of neonatal and adult Zika virus infection on startle reflex and prepulse inhibition in mice.

Zika virus (ZIKV) infection causes severe neurological consequences in both gestationally-exposed infants and adults. Sensorial gating deficits strongly correlate to the motor, sensorial and cognitive impairments observed in ZIKV-infected patients. However, no startle response or prepulse inhibition (PPI) assessment has been made in patients or animal models. In this study, we identified different outcomes according to the age of infection and sex in mice: neonatally infected animals presented an increase in PPI and delayed startle latency. However, adult-infected male mice presented lower startle amplitude, while a PPI impairment was observed 14 days after infection in both sexes. Our data further the understanding of the functional impacts of ZIKV on the developing and mature nervous system, which could help explain other behavioral and cognitive alterations caused by the virus. With this study, we support the startle reflex testing in ZIKV-exposed patients, especially infants, allowing for early detection of functional neuromotor damage and early intervention.

SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice.

Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.

Prion protein complexed to a DNA aptamer induce behavioral and synapse dysfunction in mice.

Conversion of the cellular prion protein (PrPC) into the scrapie form (PrPSc) is the leading step to the development of transmissible spongiform encephalopathies (TSEs), still incurable neurodegenerative disorders. Interaction of PrPC with cellular and synthetic ligands that induce formation of scrapie-like conformations has been deeply investigated in vitro. Different nucleic acid (NA) sequences bind PrP and convert it to ß-sheet-rich or unfolded species; among such NAs, a 21-mer double-stranded DNA, D67, was shown to induce formation of PrP aggregates that were cytotoxic. However, in vivo effects of these PrP-DNA complexes were not explored. Herein, aggregates of recombinant full-length PrP (rPrP23-231) induced by interaction with the D67 aptamer were inoculated into the lateral ventricle of Swiss mice and acute effects were investigated. The aggregates had no influence on emotional, locomotor and motor behavior of mice. In contrast, mice developed cognitive impairment and hippocampal synapse loss, which was accompanied by intense activation of glial cells in this brain region. Our results suggest that the i.c.v. injection of rPrP:D67 aggregates is an interesting model to study the neurotoxicity of aggregated PrP in vivo, and that glial cell activation may be an important step for behavioral and cognitive dysfunction in prion diseases.

SARS-CoV-2-associated cytokine storm during pregnancy as a possible risk factor for neuropsychiatric disorder development in post-pandemic infants.

A strong association between perinatal viral infections and neurodevelopmental disorders has been established. Both the direct contact of the virus with the developing brain and the strong maternal immune response originated by viral infections can impair proper neurodevelopment. Coronavirus disease 2019 (COVID-19), caused by the highly-infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a large global outbreak and is a major public health issue. While initial studies focused on the viral impact on the respiratory system, increasing evidence suggest that SARS-CoV-2 infects other organs and tissues including the mature brain. While studies continue to determine the neuropathology associated to COVID-19, the consequences of SARS-CoV-2 infection to the developing brain remain largely unexplored. The present review discusses evidence suggesting that SARS-CoV-2 infection may have persistent effects on the course of pregnancy and on brain development. Studies have shown that several proinflammatory mediators which are increased in the SARS-CoV-2-associated cytokine storm, are also modified in other viral infections known to increase the risk of neurodevelopmental disorders. In this sense, further studies should assess the genuine effects of SARS-CoV-2 infection during pregnancy and delivery along with an extended follow-up of the offspring, including neurocognitive, neuroimaging, and electrophysiological examination. It also remains to be determined whether and by which mechanisms SARS-CoV-2 intrauterine and early life infection could lead to an increased risk of developing neuropsychiatric disorders, such as autism (ASD) and schizophrenia (SZ), in the offspring.

Dissociation of genotype-dependent cognitive and motor behavior in a strain of aging mice devoid of the prion protein.

The prion glycoprotein (PrPC) is highly expressed in the nervous system as well as in other organs. Its functional roles in behavior have been examined mainly in non co-isogenic, wild-type and PrPC-deficient mice, which showed both age- and genotype-dependent differences. In general, however, effects of genetic background upon behavioral tests are mostly unclear when applied to aging rodents. The present study aimed to determine the effect of deletion of the prion protein on behavior of isogenic mice across different ages. We disclosed a genotype-dependent behavioral dissociation between either motor or cognitive tests, as a function of both age and test type. Remarkably, we also detected a clear age- and genotype-dependent difference in the variability of performance in a cognitive test. The current findings are relevant for both the interpretation of PrPC-related behavior, as well as for issues of reproducibility in studies of rodent behavior.