Fetal Neural Tissue Research Articles

Folic acid ameliorates high glucose–induced neurotoxicity in human forebrain organoids: Insights from proteomics

AbstractPregestational diabetes (PGDM) has been associated with an elevated risk of congenital abnormalities, particularly those affecting the nervous system. The efficacy of folic acid (FA) supplementation in reducing the incidence of neurodevelopmental damage caused by PGDM has been well documented. However, the exact mechanism is unclear. Here, a human forebrain organoid model, which replicates the three‐dimensional structure of the early fetal neural tissue, was employed to study the neuroprotective effects of FA in PGDM. In this study, the forebrain organoids were cultured at high glucose (HG) concentrations from Days 20 to 40 with or without FA. Immunostaining revealed that the supplementation of FA significantly decreased HG‐induced neuron apoptosis. The proteomics examination suggested HG caused an increase in glial fibrillary acidic protein expression, a marker of astrocytes, leading to the upregulation of metallothionein expression and perturbation of mineral absorption, whereas FA reversed this effect. Proteomics analysis further showed that FA reduced HG‐induced cell migration. Moreover, Western blot analysis verified that FA mitigated HG‐induced apoptosis and cell migration via AMPK/FOXO pathway. Overall, current findings indicate that FA, as a functional food ingredient, has a protective effect on HG‐induced abnormal fetal neurodevelopment.

Vitamin K Supplementation for Prevention of Teratogenic Neurological Calcification in Fetuses with Congenital Zika Syndrome: A Research Protocol

Introduction: Congenital Zika Syndrome (CZS) manifests in infants exposed to the Zika virus (ZIKV) in utero. Recent studies have documented the correlation between bone morphogenetic protein (BMP) and fetal brain calcification in these infants; however, potential treatment avenues remain unaccomplished. Unfortunately, the increase in ZIKV cases has engendered fetal neurodevelopmental defects including brain calcification which permanently impairs neurological function. The dominant pathogenic explanation results from osteogenic factor upregulation. Previous research has identified this underlying factor, highlighting the mechanism to combat the neurodegenerative impacts of ZIKV. Since the correlation between ZIKV and BMP is novel, studies addressing the mitigation of infant brain calcification are limited. Data from established ZIKV research was used to determine the potential utilization of matrix Gla protein (MGP) to inhibit the BMP pathway which calcifies fetal neural tissue. This rationale is founded on evidence showing (a) the efficacy of MGP in combating BMP-dependent calcification, and (b) the activation of MGP with Vitamin K2 (VK2). This study aims to establish a protocol for supplementing pregnant Zika patients with the VK2 derivative menaquinone-4 (MK-4), with the goal of preventing CZS-associated neurological calcification. Methods: A literature search was performed to evaluate the feasibility of VK2 injections for the prevention of neural calcification in CZS patients. The preventative potential of VK2 against CZS-related calcification will be tested using in vivo pregnant mouse (Mus musculus) models. Treatment groups will receive MK-4 administered with propylene glycol, while the control group will receive a placebo. Neurological calcification of fetuses and neonates will be monitored using pelvic ultrasound and micro-CT. Plasma and cerebral MK-4 content will be quantified using liquid chromatography-tandem mass spectrometry. Results: Anticipated results should demonstrate reduced subcortical calcification in the MK-4-treated murine cohort. Discussion: Protocol implementation precipitates the development of preventative CZS treatments. These findings indicate that low-dose maternal VK2 supplementation could provide a potential avenue for prevention of brain calcification in utero after vertical transmission of ZIKV. Conclusion: The proposed treatment would be the first of its kind, providing affected populations with a low-cost intervention for neurological damage caused by CZS, decreasing the burden of disease as ZIKV prevalence grows.

Prenatal effects of alprazolam treatment on the immature cerebellum of rats.

The use of benzodiazepines (BZDs) during pregnancy, especially alprazolam, is common and its impact on the fetal neural tissue is not known. In this sense, the present study aimed to investigate the effects of prenatal treatment with alprazolam on the cerebellum of Wistar rat pups. Thirty animals (24 females and six males, CEUA protocol 014/17) were separated into pairs for copulation. Females were divided into three groups: Control (CT), treatment 1 (T1, 1.25 mg per animal), and treatment 2, which is an overdose (T2, 30 mg per animal). Alprazolam was administered 10 days before copulation and throughout pregnancy. We evaluated the number and weight of pups and the macroscopic changes in the brain. Eight neonates (n = 8) from each group were used in the following analyses: Cellular and chromatin density, gliosis, synaptic density, inflammation, and oxidative stress. The results showed no significant differences regarding the number of pups, body weight, and macroscopic changes. The morphological study focused on the external granular layer (EGL) that is presented only in the immature cerebellum. Here, we detected more cells after alprazolam treatment; the T2 group showed large nuclei and some pyknotic nuclei; also, both treated groups presented an increase in the euchromatin density compared with the control. The molecular and biochemical analyses used the total protein extract of the entire cerebellum and showed an increased expression of Iba-1 and NF-κBp65 but without indication of inflammation or degeneration in the T1 group. Overdose of alprazolam presented an increased level of oxidative degradation of lipids. The treatment with alprazolam during pregnancy involved cellular and molecular changes in the immature cerebellum.

Revisiting cell and gene therapies in Huntington's disease.

Neurodegenerative movement disorders, such as Huntington's disease (HD), share a progressive and relentless course with increasing motor disability, linked with neuropsychiatric impairment. These diseases exhibit diverse pathophysiological processes and are a topic of intense experimental and clinical research due to the lack of therapeutic options. Restorative therapies are promising approaches with the potential to restore brain circuits. However, there were less compelling results in the few clinical trials. In this review, we discuss cell replacement therapies applied to animal models and HD patients. We thoroughly describe the initial trials using fetal neural tissue transplantation and recent approaches based on alternative cell sources tested in several animal models. Stem cells were shown to generate the desired neuron phenotype and/or provide growth factors to the degenerating host cells. Besides, genetic approaches such as RNA interference and the CRISPR/Cas9 system have been studied in animal models and human-derived cells. New genetic manipulations have revealed the capability to control or counteract the effect of human gene mutations as described by the use of antisense oligonucleotides in a clinical trial. In HD, innovative strategies are at forefront of human testing and thus other brain genetic diseases may follow similar therapeutic strategies.

Improvement of Spatial Learning and Memory Impairments by Fetal Neural Tissue Transplantation in Experimental Rat Model of Alzheimer’s Disease

ABSTRACT Objective: It is known that the acetylcholinergic afferents of the neocortex from subcortical areas participate in learning and memory. Autopsy studies in cases of Alzheimer’s disease have shown that most of the neurons of nucleus basalis magnocellularis are atrophic or decreased in number. In this study, we searched for whether or not it was possible to improve the impaired learning and memory functions with fetal neural tissue transplantation in an experimental model of Alzheimer ‘s disease. Material & Methods: A total of thirty seven young adult male Wistar albino rats were served as experimental subjects.The nucleus basalis magnocellularis on the right side was destroyed by the injection of kainic acid stereotactically so as to make a model of Alzheimer’s disease. The grafts were obtained from 14-16 day old fetuses of the same genus.After the tissue with cholinergic neurons dissected from ventral forebrain and tissue with non-cholinergic neurons dissected from telencephalic vesicle, cell suspensions were prepared and injected stereotactically to the ipsilateral frontal cortex. Spatial learnig and memory functions were tested by Morris’ water maze tasks. Results: Spatial learning and memory functions in rats were impaired by unilateral lesions of nucleus basalis magnocellularis. The impairment observed during the early period partially improved by the time. It was observed that this amelioration was accelerated with both cholinergic and non-cholinergic fetal neural tissue implantation Conclusion: In our study, improvement of spatial learning and memory impairment with both cholinergic and non-cholinergicfetal neural tissue implantation can be explained by reestablishment of impaired connections via proliferation of limited number of surviving cholinergic neurons creating new synapses, as a result of upregulation of endogenous neural stem cells and activation of trophic mechanisms by implantation, rather than creation of functional synapses between the graft andthe recipient tissue.

Decreased global DNA hydroxymethylation in neural tube defects: Association with polycyclic aromatic hydrocarbons

ABSTRACT5-Hydroxymethylcytosine (5hmC), a distinct epigenetic marker that plays a role in DNA active demethylation, has been reported to be important for embryonic development and may respond to environmental exposure. No studies have evaluated the association between DNA hydroxymethylation and the risk for fetal neural tube defects (NTDs), with consideration of prenatal exposure to polycyclic aromatic hydrocarbons (PAHs), a risk factor for NTDs.We measured the global levels of 5hmC% in neural tissue from 92 terminated NTD cases and 33 terminated non-malformed fetuses. A lower level of 5hmC% was found in the NTD cases (median [interquartile range]: 0.25 [0.12–0.39]) compared to the controls (0.45 [0.19–1.00]). After adjusting for periconceptional folate supplementation, risk for NTDs increased with decreasing tertiles of 5hmC% (odds ratio: 7.89, 95% confidence interval: 2.32, 26.86, for the lowest tertile relative to the top tertile; pfor trend = 0.002). Linear regression revealed that concentrations of high-molecular-weight PAHs (H_PAHs) in fetal liver tissue were negatively associated with log2-transformed 5hmC%. Superoxide dismutase activity and 5hmC% were positively correlated in fetal neural tissue (rs = 0.64; p < 0.05). A mouse whole-embryo culture model was used for further validation. Decreased levels of 5hmC% and increased levels of reactive oxygen species were found in mouse embryos treated with BaP, a well-studied PAH. Taken together, levels of 5hmC% in fetal neural tissue were inversely associated with the risk for NTDs, and this association may be related to oxidative stress induced by exposure to PAHs.

Maternal Antiviral Immunoglobulin Accumulates in Neural Tissue of Neonates To Prevent HSV Neurological Disease.

ABSTRACTWhile antibody responses to neurovirulent pathogens are critical for clearance, the extent to which antibodies access the nervous system to ameliorate infection is poorly understood. In this study on herpes simplex virus 1 (HSV-1), we demonstrate that HSV-specific antibodies are present during HSV-1 latency in the nervous systems of both mice and humans. We show that antibody-secreting cells entered the trigeminal ganglion (TG), a key site of HSV infection, and persisted long after the establishment of latent infection. We also demonstrate the ability of passively administered IgG to enter the TG independently of infection, showing that the naive TG is accessible to antibodies. The translational implication of this finding is that human fetal neural tissue could contain HSV-specific maternally derived antibodies. Exploring this possibility, we observed HSV-specific IgG in HSV DNA-negative human fetal TG, suggesting passive transfer of maternal immunity into the prenatal nervous system. To further investigate the role of maternal antibodies in the neonatal nervous system, we established a murine model to demonstrate that maternal IgG can access and persist in neonatal TG. This maternal antibody not only prevented disseminated infection but also completely protected the neonate from neurological disease and death following HSV challenge. Maternal antibodies therefore have a potent protective role in the neonatal nervous system against HSV infection. These findings strongly support the concept that prevention of prenatal and neonatal neurotropic infections can be achieved through maternal immunization.

Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease.

Cell therapy has attracted considerable interest as a promising therapeutic alternative for patients with Parkinson's disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation. We have previously reported that human parthenogenetic stem cell-derived neural stem cells (hpNSCs) successfully engraft, survive long term, and increase brain dopamine (DA) levels in rodent and nonhuman primate models of PD. Here we report the results of a 12-month transplantation study of hpNSCs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned African green monkeys with moderate to severe clinical parkinsonian symptoms. The hpNSCs manufactured under current good manufacturing practice (cGMP) conditions were injected bilaterally into the striatum and substantia nigra of immunosuppressed monkeys. Transplantation of hpNSCs was safe and well tolerated by the animals with no dyskinesia, tumors, ectopic tissue formation, or other test article-related serious adverse events. We observed that hpNSCs promoted behavioral recovery; increased striatal DA concentration, fiber innervation, and number of dopaminergic neurons; and induced the expression of genes and pathways downregulated in PD compared to vehicle control animals. These results provide further evidence for the clinical translation of hpNSCs and support the approval of the world's first pluripotent stem cell-based phase I/IIa study for the treatment of PD (Clinical Trial Identifier NCT02452723).

Cell therapy for neurological disorders: The elusive goal.

The positive outcomes of the transplantation of fetal neural tissue in adult rat models of a variety of neurological disorders, particularly Parkinson's disease, in the 1970s, and its translation to humans in the 1980s, raised great hopes for patients suffering from these incurable disorders. This resulted in a frantic research globally to find more suitable, reliable, and ethically acceptable alternatives. The discovery of adult stem cells, embryonic stem cells, and more recently, the induced pluripotent cells further raised our expectations. The useful functional recovery in animal models using these cell transplantation techniques coupled with the desperate needs of such patients prompted many surgeons to "jump from the rat-to-man" without scientifically establishing a proof of their utility. Each new development claimed to overcome the limitations, shortcomings, safety, and other technical problems associated with the earlier technique, yet newer difficulties prevented evidence-based acceptance of their clinical use. However, thousands of patients across the globe have received these therapies without a scientifically acceptable proof of their reliability. The present review is an attempt to summarize the current status of cell therapy for neurological disorders.

Olfactory bulb as an alternative in neurotransplantation

The article examines the ethical and legal aspects of transplantation of embryonic neural tissue, structure of the rat olfactory bulb. It is given substantiation for its use as a possible alternative version of the embryonic neural tissue at damage in the cerebral hemispheres in the experiment.Materials and methods. Detailed description of the fault model of the cerebral hemispheres of the brain of rats, olfactory bulb biopsy procedure, cultivation of olfactory bulb suspension and fetal neural tissue, comparison of the functional aspects of transplantation of the olfactory bulb and the embryonic neural tissue.Results. The obtained data are similar to structure of olfactory bulb and fetal tissues during culturing. Recovery in the motor areas varies by the time factor and less intense in the group of the olfactory bulb and the group without tissue transplantation.Conclusions. Comparative analysis of the effectiveness of transplantation of embryonic neural tissue and olfactory bulb in the injured brain allows us to speak about the positive results of these groups to the difference in the duration of the recovery process

PM-08 * A HUMANIZED CO-TRANSPLANT XENOGRAFT MOUSE MODEL, TO STUDY TOXICITY OF DRUGS TARGETED AGAINST PEDIATRIC BRAIN TUMORS

BACKGROUND: Side effects of current pediatric brain tumor therapeutics, usually resulting from neural cell toxicity, call for testing of novel therapeutic modalities on appropriate preclinical models, which recapitulates normal human neural environment with malignant brain tumors. Here, we present a new model to study toxicity of humanized antibodies against xenografted human normal neural cells sequentially co-transplanted with primary medulloblastoma (MB) cells. METHODS: Human neural progenitor cells (HuNPCs) derived from human fetal neural tissue, were infected with td-Tomato-luciferase expressing virus and injected into newborn pups (p1-p3 days old). HuNPC engraftment was confirmed with bioluminescence imaging and previously characterized for multi-potent differentiation into neurons, astrocytes and oligodendrocytes. HuNPC engrafted mice were then injected with unlabeled human MB cells at 1.5 months of age. MB cells used were previously confirmed to have 100% penetrance in multiple cohorts. After 2 weeks of tumor cell transplantation, mice were randomized and treated with either humanized anti-CD47 monoclonal antibody (HuCD47 mAb) or control. Human neural cells viability and proliferation in all mice were measured through subsequent bioluminescence imaging. RESULTS: Follow-up bioluminescence imaging revealed minimal change in flux values of treated mice with HuCD47 mAb, representing viability of engrafted normal neural cell, compared to control. Moreover, survival rates as well as subsequent H & E staining show HuCD47 mAb dramatically decreased tumor size and subsequently increased the survival of mice treated with HuCD47 mAb compared to control similar to experiments carried out in mice transplanted with human MB cells only. CONCLUSION: The presented in vivo model provides a new platform to test any novel potential therapeutic (here, HuCD47 mAb) in the context of xenografted human normal neural environment. This way we not only measure effect of the proposed drug on tumor regression but impact of developed agent on human normal neural tissue in the vicinity of the tumor.

Proof of concept studies exploring the safety and functional activity of human parthenogenetic-derived neural stem cells for the treatment of Parkinson's disease.

Recent studies indicate that human pluripotent stem cell (PSC)-based therapies hold great promise in Parkinson's disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying viable human embryos and can be used to generate an unlimited supply of neural stem cells for transplantation. Here we evaluate for the first time the safety and engraftment of human parthenogenetic stem cell-derived neural stem cells (hpNSCs) in two animal models: 6-hydroxydopamine (6-OHDA)-lesioned rodents and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates (NHPs). In both rodents and nonhuman primates, we observed successful engraftment and higher dopamine levels in hpNSC-transplanted animals compared to vehicle control animals, without any adverse events. These results indicate that hpNSCs are safe, well tolerated, and could potentially be a source for cell-based therapies in PD.

Metabolism features in the injured hemisphere after experimental traumatic brain injury and transplantation of fetal neural tissue

Metabolism features in the injured hemisphere after experimental traumatic brain injury and transplantation of fetal neural tissue

Effects of tissue neurotransplantation on sceletal muscle tone restoration after experimental mechanical injury of the cerebellum

This work aimed to conduct a comparative study of the restorative effects of transplantation of fetal neural tissue (FNT), olfactory bulb tissue (OBT) and fetal kidney (FK) on the dynamics of muscle hypotonia after cerebellar hemisphere injury in the adult rats. Beam walking test (BWT) allowed detect at least three degrees of hypotonia which correspond to 2, 3, and 4 points. The authors selected animals with function index (FI) by BWT scale strictly lesser than 4 points on the 3rd day after injury. Moderate hypotonia was associated with FI 3 points, severe – 2 points, and mild-4 points. Major differences in the dynamics of the restorative process across study groups were detected at the first month of study: slow recovery of statics and coordination (control); fast recovery (during first 9 days, FK, OBT and FNT groups) that underwent changes by its slow increase during 9th–33rd day. Mild hypotonia in the control group showed itself by the end of the 1st month and on the 9th day in the FK, OBT and FNT groups. Normotony was observed on the 21st (group FNT) and 30th day (groups FK and OBT). These data suggest that neurotransplantation has a significant effect on muscle tone improvement after cerebellar injury, depending on the type of graft.

Effect of fetal cells of the nervous tissue during postresuscitational encephalopathy in rats of different sex and ages

The aim of the study was to examine the comparative aspect of the influence of the intraperitoneal injection of fetal cells in the nervous tissue during postresuscitational encephalopathy in rats of different sex and age. For the purposes of investigating the qualitative and quantitative composition of phospholipids lipid extraction of the cerebral cortex was produced based on the method of J. Falchion (Folch J. et al., 1957) and fractionation of phospholipids (PL) based on the thin layer chromatography on silica gel. The study revealed that the intraperitoneal injection of a suspension of fetal neural cells accelerates the rate of replenishment of neurological deficit and increases survival reanimated males of all ages.The introduction of fetal nerve cells improves the spectral composition of phospholipids in brain homogenate lively males and worsens at reanimated females. Repeated injection of cells of fetal neural tissue leads in all experimental groups to the adverse redistribution of fractions of phospholipids.

Novel assessment of a novel meningitis B vaccine

Invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) most commonly affects infants,1,2 but a vaccine has long eluded vaccinologists. The main barrier has been the B polysaccharide. The serogroup A, C, W-135, and Y polysaccharides are highly immunogenic and licensed vaccines are available. By contrast, the group B polysaccharide has antigenic similarities with glycoproteins expressed by fetal neural tissue that render it non-immunogenic in human beings.3 The novel multicomponent protein-based vaccine against MenB, 4CMenB, circumvents this barrier with a cocktail of three surface-expressed protein antigens: factor-H-binding protein variant 1, neisserial heparin-binding antigen, and neisserial adhesin A.

Maternal consumption of a DHA-containing functional food benefits infant sleep patterning: An early neurodevelopmental measure

BackgroundDocosahexaenoic acid (DHA; 22:6n−3) is highly important during pregnancy for optimal development and functioning of fetal neural tissue. Infant ability to organize sleep and wake states following parturition is highly associated with later developmental outcomes. The impact of maternal DHA intake on sleep organization has not been previously investigated. AimsTo examine the effect of a DHA-containing functional food consumed during pregnancy on early neurobehavioral development as assessed by infant sleep patterning in the first 48 postnatal hours. Study designA longitudinal, randomized, double-blinded, placebo-controlled design was used. SubjectsWomen (18–35y) with no pregnancy complications consumed a cereal-based functional food (92kcal) containing 300mg DHA an average of 5d/week or placebo bars (n=27 DHA, n=21 Placebo). The intervention began at 24weeks gestation and continued until delivery (38–40weeks). Outcome measuresInfant sleep/wake states were measured on postnatal days 1 (D1) and 2 (D2) using a pressure sensitive mattress recording respiration and body movements. ResultsUsing ANCOVA and controlling for ethnic variation, there were significant group differences in arousals in quiet sleep on D1 (P=0.006) and D2 (P=0.011) with fewer arousals in the DHA intervention group compared to the placebo group. Similarly, arousals in active sleep on D1 were significantly lower in the DHA-intervention group (P=0.012) compared to the placebo group. ConclusionsWe conclude that increased prenatal supply of dietary DHA has a beneficial impact on infant sleep organization.

Impact of Late Transplantation of Fetal Neural Tissue on Hippocampal Cytoarchitectonics in Remote Period after Transient Global Cerebral Ischemia in Rats

Impact of Late Transplantation of Fetal Neural Tissue on Hippocampal Cytoarchitectonics in Remote Period after Transient Global Cerebral Ischemia in Rats

Human Glial-Restricted Progenitor Transplantation into Cervical Spinal Cord of the SOD1G93A Mouse Model of ALS

Cellular abnormalities are not limited to motor neurons in amyotrophic lateral sclerosis (ALS). There are numerous observations of astrocyte dysfunction in both humans with ALS and in SOD1G93A rodents, a widely studied ALS model. The present study therapeutically targeted astrocyte replacement in this model via transplantation of human Glial-Restricted Progenitors (hGRPs), lineage-restricted progenitors derived from human fetal neural tissue. Our previous findings demonstrated that transplantation of rodent-derived GRPs into cervical spinal cord ventral gray matter (in order to target therapy to diaphragmatic function) resulted in therapeutic efficacy in the SOD1G93A rat. Those findings demonstrated the feasibility and efficacy of transplantation-based astrocyte replacement for ALS, and also show that targeted multi-segmental cell delivery to cervical spinal cord is a promising therapeutic strategy, particularly because of its relevance to addressing respiratory compromise associated with ALS. The present study investigated the safety and in vivo survival, distribution, differentiation, and potential efficacy of hGRPs in the SOD1G93A mouse. hGRP transplants robustly survived and migrated in both gray and white matter and differentiated into astrocytes in SOD1G93A mice spinal cord, despite ongoing disease progression. However, cervical spinal cord transplants did not result in motor neuron protection or any therapeutic benefits on functional outcome measures. This study provides an in vivo characterization of this glial progenitor cell and provides a foundation for understanding their capacity for survival, integration within host tissues, differentiation into glial subtypes, migration, and lack of toxicity or tumor formation.

The Role of Microbial Agents in the Etiology of Schizophrenia: An Infectious Hypothesis for Psychosis?

The ultimate cause of schizophrenia remains to be found, but it clearly includes a significant genetic component with an estimated heritability up to 85%. This suggests that genes may act as a predisposing factor upon which a variety of environmental risk factors can exert their deleterious effects, determining the emergence of psychotic symptoms. A recently growing interest has re-arisen on perinatal brain infections, which may increase the risk for schizophrenia that can, in turn, be modified by hazardous genetic loading. This hypothesis is based on epidemiological evidence, which has shown a significant exposure of affected individuals to infections with different pathogens. Such results are supported by tests carried out on animals. Another possibility is that there may be a link between a primary maternal infection and the subsequent development of schizophrenia in offspring. It is also been hypothesized that maternal antibodies against microorganisms may damage the fetal neural tissue, the area which is later found to be affected by the lesion occurring in patients with schizophrenia. In the present chapter, we review recent evidence on the potential role of infectious agents in the etiology of schizophrenia and discuss possible implications on the future of diagnostic, preventive and therapeutic issues.