Attractive action of FGF-signaling contributes to the postnatal developing hippocampus.

During brain development neural cell migration is a crucial, well-orchestrated, process, which leads to the proper whole brain structural organization. As development proceeds, new neurons are continuously produced, and this protracted neurogenesis is maintained throughout life in specialized germinative areas inside the telencephalon: the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. In the anterior SVZ, newly generated neurons migrate through long distances, along the rostral migratory stream (RMS), before reaching their final destinations in the olfactory bulb (OB). Intriguingly, recent observations pointed out the existence of other postnatal tangential routes of migration alternative to the RMS but still starting from the SVZ. The presence of such dynamic and heterogeneous cell movements contributes to important features in the postnatal brain such as neural cell replacement and plasticity in cortical regions. In this work, we asked whether a caudal migratory pathway starting from the caudal SVZ continues through life. Strikingly, in vivo analysis of this caudal migration revealed the presence of a postnatal contribution of SVZ to the hippocampus. In vitro studies of the caudal migratory stream revealed the role of FGF signaling in attracting caudally the migrating neuroblasts during postnatal stages. Our findings demonstrate a postnatal neuronal contribution from the caudal ganglionic eminence (CGE) CGE-SVZ to the hippocampus through an FGF-dependent migrating mechanism. All together our data emphasizes the emerging idea that a developmental program is still operating in discrete domains of the postnatal brain and may contribute to the regulation of neural cell replacement processes in physiological plasticity and/or pathological circumstances.

Human embryonic stem cell-derived neurons establish region-specific, long-range projections in the adult brain.

While the availability of pluripotent stem cells has opened new prospects for generating neural donor cells for nervous system repair, their capability to integrate with adult brain tissue in a structurally relevant way is still largely unresolved. We addressed the potential of human embryonic stem cell-derived long-term self-renewing neuroepithelial stem cells (lt-NES cells) to establish axonal projections after transplantation into the adult rodent brain. Transgenic and species-specific markers were used to trace the innervation pattern established by transplants in the hippocampus and motor cortex. In vitro, lt-NES cells formed a complex axonal network within several weeks after the initiation of differentiation and expressed a composition of surface receptors known to be instrumental in axonal growth and pathfinding. In vivo, these donor cells adopted projection patterns closely mimicking endogenous projections in two different regions of the adult rodent brain. Hippocampal grafts placed in the dentate gyrus projected to both the ipsilateral and contralateral pyramidal cell layers, while axons of donor neurons placed in the motor cortex extended via the external and internal capsule into the cervical spinal cord and via the corpus callosum into the contralateral cortex. Interestingly, acquisition of these region-specific projection profiles was not correlated with the adoption of a regional phenotype. Upon reaching their destination, human axons established ultrastructural correlates of synaptic connections with host neurons. Together, these data indicate that neurons derived from human pluripotent stem cells are endowed with a remarkable potential to establish orthotopic long-range projections in the adult mammalian brain.

Intrahippocampal transplantation of mesenchymal stromal cells promotes neuroplasticity.

BACKGROUND AIMS: Multipotent mesenchymal stromal cells (MSC) secrete soluble factors that stimulate the surrounding microenvironment. Such paracrine effects might underlie the potential benefits of many stem cell therapies. We tested the hypothesis that MSC are able to enhance intrinsic cellular plasticity in the adult rat hippocampus. METHODS: Rat bone marrow-derived MSC were labeled with very small superparamagnetic iron oxide particles (VSOP), which allowed for non-invasive graft localization by magnetic resonance imaging (MRI). Moreover, MSC were transduced with lentiviral vectors to express the green fluorescent protein (GFP). The effects of bilateral MSC transplantation on hippocampal cellular plasticity were assessed using the thymidine analogs 5-bromo-2'-deoxyuridine (BrdU) and 5-iodo-2'-deoxyuridine (IdU). Behavioral testing was performed to examine the consequences of intrahippocampal MSC transplantation on locomotion, learning and memory, and anxiety-like and depression-like behavior. RESULTS: We found that intrahippocampal transplantation of MSC resulted in enhanced neurogenesis despite short-term graft survival. In contrast, systemic administration of the selective serotonin re-uptake inhibitor citalopram increased cell survival but did not affect cell proliferation. Intrahippocampal transplantation of MSC did not impair behavioral functions in rats, but only citalopram exerted anti-depressant effects. CONCLUSIONS: This is the first study to examine the effects of intrahippocampal transplantation of allogeneic MSC on hippocampal structural plasticity and behavioral functions in rats combined with non-invasive cell tracking by MRI. We found that iron oxide nanoparticles can be used to detect transplanted MSC in the brain. Although graft survival was short, intrahippocampal transplantation of MSC resulted in long-term changes in hippocampal plasticity. Our results suggest that MSC can be used to stimulate adult neurogenesis.

Blueberry supplementation attenuates microglial activation in hippocampal intraocular grafts to aged hosts.

Transplantation of central nervous tissue has been proposed as a therapeutic intervention for age-related neurodegenerative diseases and stroke. However, survival of embryonic neuronal cells is hampered by detrimental factors in the aged host brain such as circulating inflammatory cytokines and oxidative stress. We have previously found that supplementation with 2% blueberry in the diet increases graft growth and neuronal survival in intraocular hippocampal grafts to aged hosts. In the present study we explored possible biochemical mechanisms for this increased survival, and we here report decreased microglial activation and astrogliosis in intraocular hippocampal grafts to middle-aged hosts fed a 2% blueberry diet. Markers for astrocytes and for activated microglial cells were both decreased long-term after grafting to blueberry-treated hosts compared with age-matched rats on a control diet. Similar findings were obtained in the host brain, with a reduction in OX-6 immunoreactive microglial cells in the hippocampus of those recipients treated with blueberry. In addition, immunoreactivity for the pro-inflammatory cytokine IL-6 was found to be significantly attenuated in intraocular grafts by the 2% blueberry diet. These studies demonstrate direct effects of blueberry upon microglial activation both during isolated conditions and in the aged host brain and suggest that this nutraceutical can attenuate age-induced inflammation.

Intrahippocampal septal grafts ameliorate learning impairments in aged rats.

Grafts of fetal septal tissue rich in cholinergic neurons were implanted as a dissociated cell suspension into the depth of the hippocampal formation in aged rats with severe impairments in spatial learning abilities. After 2 1/2 to 3 months, the rats with grafts, but not the controls, had improved their performance in a spatial learning test. Their improvement was due, at least in part, to an increased ability to use spatial cues in the task. In all animals the grafts had produced an extensive acetylcholinesterase-positive terminal network in the surrounding host hippocampal formation. Thus, the action of cholinergic neurons in the graft onto elements in the host hippocampal circuitry may be a necessary, but perhaps not sufficient, prerequisite for the observed functional recovery.

[Morpho-functional interactions of the iris peripheral nervous fibers with the neurons developing in the rat anterior eye chamber].

The intraocular grafts of the septal or hippocampal embryonic tissues developing in the rat anterior eye chamber for three to four months were investigated by electron microscopy. The aim of this study was both the ultrastructural identification of the peripheral nervous fibers entering the grafts from host iris and the estimation of their capacity to establish true synaptic contacts with the central nervous system neurons of the grafts. The bundles of myelinated and unmyelinated axons, surrounded by the Schwann cell cytoplasm, were observed within the perivascular spaces of the ingrowing blood vessels. In the neuropil areas of the grafts, both types of the peripheral nervous fibers were also identified. It was demonstrated on the ultrastructural level that the unmyelinated axons lost their glial envelope of the Schwann cell and formed the typical asymmetric synapses with the dendrites and dendritic spines of the grafted neurons. The results are indicative of the high morpho-functional plasticity of both parts of the nervous system.

Intrahippocampal transplantation of transgenic neural precursor cells overexpressing interleukin-1 receptor antagonist blocks chronic isolation-induced impairment in memory and neurogenesis.

The proinflammatory cytokine interleukin-1 (IL-1) within the brain is critically involved in mediating the memory impairment induced by acute inflammatory challenges and psychological stress. However, the role of IL-1 in memory impairment and suppressed neurogenesis induced by chronic stress exposure has not been investigated before now. We report here that mice that were isolated for 4 weeks displayed a significant elevation in hippocampal IL-1beta levels concomitantly with body weight loss, specific impairment in hippocampal-dependent memory, and decreased hippocampal neurogenesis. To examine the causal role of IL-1 in these effects, we developed a novel approach for long-term delivery of IL-1 receptor antagonist (IL-1ra) into the brain, using transplantation of neural precursor cells (NPCs), obtained from neonatal mice with transgenic overexpression of IL-1ra (IL-1raTG) under the glial fibrillary acidic protein promoter. Four weeks following intrahippocampal transplantation of IL-1raTG NPCs labeled with PKH-26, the transplanted cells were incorporated within the dentate gyrus and expressed mainly astrocytic markers. IL-1ra levels were markedly elevated in the hippocampus, but not in other brain regions, by 10 days and for at least 4 weeks post-transplantation. Transplantation of IL-1raTG NPCs completely rescued the chronic isolation-induced body weight loss, memory impairment, and suppressed hippocampal neurogenesis, compared with isolated mice transplanted with WT cells or sham operated. The transplantation had no effect in group-housed mice. These findings elucidate the role of IL-1 in the pathophysiology of chronic isolation and suggest that transplantation of IL-1raTG NPCs may provide a useful therapeutic procedure for IL-1-mediated memory disturbances in chronic inflammatory and neurological conditions.

Extracellular amyloid formation and associated pathology in neural grafts.

Amyloid precursor protein (APP) processing and the generation of beta-amyloid peptide (Abeta) are important in the pathogenesis of Alzheimer's disease. Although this has been studied extensively at the molecular and cellular levels, much less is known about the mechanisms of amyloid accumulation in vivo. We transplanted transgenic APP23 and wild-type B6 embryonic neural cells into the neocortex and hippocampus of both B6 and APP23 mice. APP23 grafts into wild-type hosts did not develop amyloid deposits up to 20 months after grafting. In contrast, both transgenic and wild-type grafts into young transgenic hosts developed amyloid plaques as early as 3 months after grafting. Although largely diffuse in nature, some of the amyloid deposits in wild-type grafts were congophilic and were surrounded by neuritic changes and gliosis, similar to the amyloid-associated pathology previously described in APP23 mice. Our results indicate that diffusion of soluble Abeta in the extracellular space is involved in the spread of Abeta pathology, and that extracellular amyloid formation can lead to neurodegeneration.

Repair of the injured adult hippocampus through graft-mediated modulation of the plasticity of the dentate gyrus in a rat model of temporal lobe epilepsy.

Intracerebroventricular kainate administration in rat, a model of temporal lobe epilepsy (TLE), causes degeneration of the hippocampal CA3 pyramidal and dentate hilar neurons. This leads to a robust but aberrant sprouting of the granule cell axons (mossy fibers) into the dentate supragranular layer and the CA3 stratum oriens. Because this plasticity is linked to an increased seizure susceptibility in TLE, strategies that restrain the aberrant mossy fiber sprouting (MFS) are perceived to be important for preventing the TLE development after the hippocampal injury. We ascertained the efficacy of fetal hippocampal CA3 or CA1 cell grafting into the kainate-lesioned CA3 region of the adult rat hippocampus at early post-kainic acid injury for providing a lasting inhibition of the aberrant MFS. Analyses at 12 months after grafting revealed that host mossy fibers project vigorously into CA3 cell grafts but avoid CA1 cell grafts. Consequently, in animals receiving CA3 cell grafts, the extent of aberrant MFS was minimal, in comparison with the robust MFS observed in both "lesion-only" animals and animals receiving CA1 cell grafts. Analyses of the graft axon growth revealed strong graft efferent projections into the dentate supragranular layer with CA3 cell grafting but not with CA1 cell grafting. Thus, the formation of reciprocal circuitry between the dentate granule cells and the grafted CA3 pyramidal neurons is likely the basis of inhibition of the aberrant MFS by CA3 cell grafts. The results also underscore that grafting of cells capable of differentiating into CA3 pyramidal neurons is highly efficacious for a lasting inhibition of the abnormal mossy fiber circuitry development in the injured hippocampus.

The neuropathology of Alzheimer's disease investigated by transplantation of mouse trisomy 16 hippocampal tissues.

This article evaluates the novel application of neural transplantation as a model for studying the neuropathological events associated with Alzheimer's disease and those that have subsequently also been observed in Trisomy 21 (Down syndrome).

Cholinergic grafts, memory and ageing.

Neural grafts rich in cholinergic neurones can survive transplantation to the neocortex or hippocampus in rats. Such grafts have the capacity to ameliorate a variety of functional deficits associated both with explicit lesions that deafferent the neocortex or hippocampus and with natural ageing. The transplantation technique enhances our understanding of the involvement of forebrain cholinergic systems in normal cognitive functions (including memory) and of the role of cholinergic degeneration in the dysfunctions associated with ageing. It is unlikely, however, that these observations will extend to a therapeutic strategy for dementia using neural transplantation, because the human diseases (at least in the case of Alzheimer's disease and multi-infarct dementia) involve widespread degeneration of other populations of cortical neurones that are not so amenable to functional transplantation as the diffuse forebrain cholinergic systems.

Development of fetal hippocampal grafts in intact and lesioned hippocampus.

Functional recovery observed in Parkinson's disease patients following grafting of fetal substantia nigra has encouraged the development of similar grafting therapy for other neurological disorders. Fetal hippocampal grafting paradigms are of considerable significance because of their potential to treat neurological disorders affecting primarily hippocampus, including temporal lobe epilepsy, cerebral ischemia, stroke, and head injury. Since many recent studies of hippocampal transplants were carried out with an aim of laying the foundation for future clinical applications, an overview of the development of fetal hippocampal transplants, and their capability for inducing functional recovery under different host conditions is timely. In this review, we will summarize recent developments in hippocampal transplants, especially the anatomical and/or functional integration of grafts within the host brain under specific host conditions, including a comparison of intact hippocampus with various types of hippocampal lesions or injury. Improvements in grafting techniques, methods for analysis of graft integration and graft function will be summarized, in addition to critical factors which enhance the survival and integration of grafted cells and alternative sources of donor cells currently being tested or considered for hippocampal transplantation. Viewed collectively, hippocampal grafting studies show that fetal hippocampal tissue/cells survive grafting, establish both afferent and efferent connections with the host brain, and are also capable of ameliorating certain learning and memory deficits in some models. However, the efficacy of intracerebral fetal hippocampal grafts varies considerably in different animal models, depending on several factors: the mode of donor tissue preparation, the method of grafting, the state of host hippocampus at the time of grafting, and the placement of grafts within the hippocampus. Functional improvement in many models appeared to be caused partially by re-establishment of damaged circuitry and partially by a trophic action of grafts. However, exact mechanisms of graft-mediated behavioral recovery remain to be clarified due to the lack of correlative analysis in the same animal between the degree of graft integration and behavioral recovery. Issues of mechanisms of action, degree of restoration of host circuitry and amelioration of host pathological conditions will need to be sorted out clearly prior to clinical use of fetal hippocampal transplants for susceptible neurological conditions.

Fetal hippocampal grafts containing CA3 cells restore host hippocampal glutamate decarboxylase-positive interneuron numbers in a rat model of temporal lobe epilepsy.

Degeneration of CA3-pyramidal neurons in hippocampus after intracerebroventricular kainic acid (KA) administration, a model of temporal lobe epilepsy, results in hyperexcitability within both dentate gyrus and the CA1 subfield. It also leads to persistent reductions in hippocampal glutamate decarboxylase (GAD) interneuron numbers without diminution in Nissl-stained interneuron numbers, indicating loss of GAD expression in a majority of interneurons. We hypothesize that enduring loss of GAD expression in hippocampal interneurons after intracerebroventricular KA is attributable to degeneration of their CA3 afferent input; therefore, fetal CA3 grafts can restore GAD interneuron numbers through graft axon reinnervation of the host. We analyzed GAD interneuron density in the adult rat hippocampus at 6 months after KA administration after grafting of fetal mixed hippocampal, CA3 or CA1 cells into the CA3 region at 45 d after lesion, in comparison with "lesion-only" and intact hippocampus. In dentate and CA1 regions of the lesioned hippocampus receiving grafts of either mixed hippocampal or CA3 cells, GAD interneuron density was both significantly greater than lesion-only hippocampus and comparable with the intact hippocampus. In the CA3 region, GAD interneuron density was significantly greater than lesion-only hippocampus but less than the intact hippocampus. Collectively, the overall GAD interneuron density in the lesioned hippocampus receiving either mixed hippocampal or CA3 grafts was restored to that in the intact hippocampus. In contrast, GADinterneuron density in the lesioned hippocampus receiving CA1 grafts remained comparable with lesion-only hippocampus. Thus, grafts containing CA3 cells restore CA3 lesion-induced depletions in hippocampal GAD interneurons, likely by reinnervation of GAD-deficient interneurons. This specific graft-mediated effect is beneficial because reactivation of interneurons could ameliorate both loss of functional inhibition and hyperexcitability in CA3-lesioned hippocampus.

Blueberry extract enhances survival of intraocular hippocampal transplants.

Transplantation of neural tissue has been explored as a potential therapy to replace dead or dying cells in the brain, such as after brain injury or neurodegenerative disease. However, survival of transplanted tissue is poor, especially when the transplant recipient is of advanced age. Recent studies have demonstrated improvement of neuronal deficits in aged animals given a diet supplemented with blueberry extract. The present study focuses on the survival of fetal hippocampal transplants to young (4 months) or middle-aged (16 months) animals with or without dietary supplementation with blueberry extract. Results indicate that fetal hippocampus transplanted to middle-aged host animals exhibits poor survival characterized by reduced growth and compromised tissue organization. However, when middle-aged animals were maintained on a diet supplemented with 2% blueberry extract, hippocampal graft growth was significantly improved and cellular organization of grafts was comparable to that seen in tissue grafted to young host animals. Thus, the data suggest that factor(s) in blueberries may have significant effects on development and organization of this important brain region.

Regulation of trophic factor expression by innervating target regions in intraocular double transplants.

Trophic factors have been found to play a significant role both in long-term survival processes and in more rapid and dynamic processes in the brain and spinal cord. However, little is known regarding the regulation of expression of growth factors, and how these proteins interact on a cell-to-cell basis. We have studied protein levels of one growth factor known to affect the noradrenergic innervation of the hippocampal formation, namely brain-derived neurotrophic factor (BDNF). The purpose of the present study was to determine if appropriate innervation or contact between the LC noradrenergic neurons and their target, the hippocampus, affects expression of this growth factor in either brain region. Fetal brain stem tissue, containing the LC, and hippocampal formation were dissected from embryonic day 17 rat fetuses and transplanted together or alone into the anterior chamber of the eye of adult Fisher 344 rats. The tissue was grown together for 6 weeks, after which the animals were sacrificed and ELISAs for BDNF were undertaken. Transplantation to the anterior chamber of the eye increased the expression of BDNF in the hippocampal but not the brain stem tissue, compared with levels observed in fetal and adult rats in vivo. In addition, double grafting with hippocampal tissue more than tripled BDNF levels in brain stem grafts and doubled BDNF levels in the hippocampal portion of double grafts compared with hippocampal single grafts. Triple grafts containing basal forebrain, hippocampus, and brain stem LC tissue increased brain stem and hippocampal BDNF levels even further. Colchicine treatment of LC-hippocampal double grafts gave rise to a significant decrease in hippocampal BDNF levels to levels seen in single hippocampal grafts, while only a partial reduction of BDNF levels was seen in the brain stem portion of the same double grafts treated with colchicine. The findings suggest that an appropriate hippocampal innervation or contact with its target tissues is essential for regulation of BDNF expression in the brain stem, and that retrograde transport of BDNF can occur between double grafted fetal tissues in oculo.

The hippocampus and neurotransplantation.

The present article is a review of our own results from histological and electron microscopic studies of hippocampal neurotransplants with different levels of integration with recipient brains. A model providing complete isolation from the brain was obtained using transplants developing in the anterior chamber of the eye. The growth, development, and cytological composition of transplanted tissue was found to depend on factors such as the age of the donor embryo tissue, the genetic compatibility between the donor and recipient, and the level of integration with the brain. Ultrastructural analysis of intraocular and intracortical transplants showed that overall, nerve and glial cells have the characteristics of highly differentiated, mature elements; the numerical density and structures of synaptic contacts were similar to those in normal conditions. However, transplanted tissues contained morphological features providing evidence of continuing growth of several nerve processes and increases in non-synaptic and transport-metabolic intercellular interactions. The ultrastructural deviations observed here are regarded as the manifestations of compensatory-adaptive changes during the development of tissues in conditions deficient in natural afferent synaptic influences. It is also demonstrated that the axons of transplanted neurons lacking adequate cellular targets can establish functional synaptic contacts with neuronal elements in the recipient brain which are not their normal targets.

Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction.

The frequent use of chemotherapy to combat a range of malignancies can elicit severe cognitive dysfunction often referred to as "chemobrain," a condition that can persist long after the cessation of treatment in as many as 75% of survivors. Although cognitive health is a critical determinant of therapeutic outcome, chemobrain remains an unmet medical need that adversely affects quality of life in pediatric and adult cancer survivors. Using a rodent model of chemobrain, we showed that chronic cyclophosphamide treatment induced significant performance-based decrements on behavioral tasks designed to interrogate hippocampal and cortical function. Intrahippocampal transplantation of human neural stem cells resolved all cognitive impairments when animals were tested 1 month after the cessation of chemotherapy. In transplanted animals, grafted cells survived (8%) and differentiated along neuronal and astroglial lineages, where improved cognition was associated with reduced neuroinflammation and enhanced host dendritic arborization. Stem cell transplantation significantly reduced the number of activated microglia after cyclophosphamide treatment in the brain. Granule and pyramidal cell neurons within the dentate gyrus and CA1 subfields of the hippocampus exhibited significant reductions in dendritic complexity, spine density, and immature and mature spine types following chemotherapy, adverse effects that were eradicated by stem cell transplantation. Our findings provide the first evidence that cranial transplantation of stem cells can reverse the deleterious effects of chemobrain, through a trophic support mechanism involving the attenuation of neuroinflammation and the preservation host neuronal architecture.

Propagation of Neuronal Damage to Embryonic Grafts Transplanted in the Hippocampus of Murine Models of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia, characterized by the presence of two principal hallmarks-amyloid plaques and neurofibrillary tangles. The primary cause of the majority of AD cases is not known. Likewise, the mechanisms underlying the propagation of the pathology from affected tissue to neighboring healthy neurons are largely unknown, but knowledge about them could be helpful to design strategies aimed at halting the progression of the disease. To throw light on the mechanisms of propagation of neuronal damage to healthy tissue, wild-type (WT) hippocampal solid tissue chunks derived from green fluorescent protein (GFP)-positive embryos were grafted into the hippocampus of 6-month-old WT and 3xTg-AD mice, a triple-transgenic mouse model that exhibits both amyloid-beta (Aß) and tau protein pathology. The histological and morphological alterations of the grafted tissues were assessed 3 months post-transplantation. Tissues grafted in 3xTg-AD hosts, compared to those grafted in WT recipients, presented a significant decrease in neurite outgrowth (35.4%) and dendritic spine density (41.3%), mainly due to a reduction of stubby and thin-shaped spines. Moreover, some cells of the tissue transplanted in 3xTg-AD hosts accumulated intracellular amyloid peptide deposits similar to the cells of the host. Furthermore, the immunohistochemical examination of reactive astrocytes and microglia revealed the presence of more inflammation in the grafted tissues hosted in 3xTg-AD compared to WT recipients. These results show a propagation of neuronal damage to initially healthy embryonic grafts, validating this methodology for future studies on the mechanisms of the progression of AD pathology to surrounding regions.

Neural transplantation as an experimental treatment modality for cerebral ischemia.

Cerebrovascular disease exemplifies the poor regenerative capacity of the CNS. While there are methods to prevent cerebral infarction, there is no effective therapy available to ameliorate the anatomical, neurochemical and behavioral deficits which follow cerebral ischemia. Focal and transient occlusion of the middle cerebral artery (MCA) in rodents has been reported to result in neuropathology similar to that seen in clinical cerebral ischemia. Using specific techniques, this MCA occlusion can result in a well-localized infarct of the striatum. This review article will provide data accumulated from animal studies using the MCA occlusion technique in rodents to examine whether neural transplantation can ameliorate behavioral and morphological deficits associated with cerebral infarction. Recent advances in neural transplantation as a treatment modality for neurodegenerative disorders such as Parkinson's disease, have revealed that fetal tissue transplantation may produce neurobehavioral recovery. Accordingly, fetal tissue transplantation may provide a potential therapy for cerebral infarction. Preliminary findings in rodents subjected to unilateral MCA occlusion, and subsequently transplanted with fetal striatal tissue into the infarcted striatum have produced encouraging results. Transplanted fetal tissue, assessed immunohistochemically, has been demonstrated to survive and integrate with the host tissue, and, more importantly, ameliorate the ischemia-related behavioral deficits, at least in the short term. Although, this review will focus primarily on cerebral ischemia, characterized by a localized CNS lesion within the striatum, it is envisioned that this baseline data may be extrapolated and applied to cerebral infarction in other brain areas.

Initial studies of embryonic transplants of human hippocampus and cerebral cortex derived from schizophrenic women.

Human fetal brain tissue was obtained from first-trimester elective abortions of two women who also had schizophrenia. Portions of the embryonic hippocampus or cerebral cortex were transplanted into the anterior eye chamber of immunologically compromised athymic nude rats. In this environment, embryonic brain tissue derived from normal women generally continues organotypic growth and development for many months. Although initial survival after transplantation was normal, the tissue derived from schizophrenic women manifested less robust growth. However, cells in the transplants showed typical neuronal differentiation, with development of different neuronal types, such as pyramidal cells, granule cells, and gamma-aminobutyric acid (GABA)-containing interneurons. Rhythmic electrical activity was also observed, indicative of some local synaptic organization. The presence of messenger RNA (mRNA) for brain-derived neuronotrophic factor (BDNF) was observed using in situ hybridization. The reason for the decreased rate of growth of these transplants remains unknown and the significance of the finding cannot be assessed from only two fetuses. However, these preliminary findings suggest that fetal transplants may be a useful model system for the detection of developmental pathogenic processes in the expression and transmission of schizophrenia.