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PubMed1992

Transcriptional regulation of glial fibrillary acidic protein (GFAP)-mRNA expression during postnatal development of mouse brain.

During mouse brain maturation, GFAP-mRNA undergoes a two-step developmental expression. It increases between birth and day 15 (period of astrocytic proliferation) and then decreases until day 55 (period of astrocytic morphological differentiation). We have developed an in vitro transcription procedure, as a mean to study the part of transcriptional control in this biphasic expression. After RNA synthesis by endogenous RNA polymerases in nuclei isolated from mouse brain (of 3 to 55 days and 217 days), the relative rates of GFAP-mRNA transcripts were analysed by hybridization with a specific cDNA probe. As early as 3 days after birth, the rate of GFAP-mRNA transcripts was maximal, whereas unexpectedly, it showed a significant decrease in mice of 15 days and stayed low until the 55th day. Therefore, a transcriptional control may take place early in mouse brain postnatal development by increasing the transcriptional rate of the GFAP gene in astrocytes, and during the transition from proliferation to differentiation phase of astrocytes (that occurs at the 15th day after birth) by decreasing this rate. However, posttranscriptional events may also occur to modulate the level of the cytoplasmic GFAP-mRNA. In older mice (217 days), the low rate of GFAP-mRNA transcripts found is not concordant with the high cytoplasmic level generally observed in gliosis of the aging brain. Our data suggest posttranscriptional events at this age.

Aging↗
PubMed2001

The antioxidant enzyme quinone reductase is up-regulated in vivo following cerebral ischemia.

An astrocyte antioxidant enzyme, quinone reductase (QR), was studied in vivo to assess whether its activity was up-regulated following cerebral ischemia. Rats were given a unilateral focal cerebral infarct and regions of interest within the ischemic penumbra compared to the non-ischemic side for QR activity. At 7 days post-ischemia, QR activity was significantly up-regulated within cells of astrocyte morphology in the cortex (p = 0.007) and subcortical (p = 0.005) areas adjacent to the infarct. This enzyme activity peaked at 7 days but was still significantly up-regulated at 14 days. Up-regulation of QR activity occurs within the ischemic penumbra of a stroke in this animal model and may contribute to factors that limit ischemic damage to neurons in this area.

Animals↗
PubMed1994

Astrocytosis and axonal proliferation in the hippocampus of S100b transgenic mice.

S100 beta is a calcium-binding protein that is expressed at high levels in brain primarily by astrocytes. Addition of the disulfide-bonded dimeric form of S100 beta to primary neuronal and glial cultures and established cell lines induces axonal extension and alterations in astrocyte proliferation and phenotype, but evidence that S100 beta exerts the same effects in vivo has not been presented. An 8.9-kb murine S100b genomic clone was used to produce two lines of transgenic mice in which S100 beta RNA is increased in a dose-related manner to 2-fold and 7-fold above normal. These lines show concomitant increased S100 beta protein throughout the brain. Expression in both lines is cell type- and tissue-appropriate, and expression levels are correlated with the transgene copy number, demonstrating that sequences necessary for normal regulation of the gene are included within the cloned segment. In the hippocampus of adult transgenic mice, Western blotting detects elevated levels of glial fibrillary acidic protein and several markers of axonal sprouting, including neurofilament L, phosphorylated epitopes of neurofilament H and M, and beta-tubulin. Immunocytochemistry demonstrates alterations in astrocyte morphology and axonal sprouting, especially in the dentate gyrus. Thus, both astrocytosis and neurite proliferation occur in transgenic mice expressing elevated levels of S100 beta. These transgenic mice provide a useful model for studies of the role of S100 beta in glial-neuronal interactions in normal development and function of the brain and for analyzing the significance of elevated levels of S100 beta in Down syndrome and Alzheimer disease.

Animals↗
PubMed1993

Okadaic acid induces early changes in microtubule-associated protein 2 and tau phosphorylation prior to neurodegeneration in cultured cortical neurons.

Microtubules and their associated proteins play a prominent role in many physiological and morphological aspects of brain function. Abnormal deposition of the microtubule-associated proteins (MAPs), MAP2 and tau, is a prominent aspect of Alzheimer's disease. MAP2 and tau are heat-stable phosphoproteins subject to high rates of phosphorylation/dephosphorylation. The phosphorylation state of these proteins modulates their affinity for tubulin and thereby affects the structure of the neuronal cytoskeleton. The dinoflagellate toxin okadaic acid is a potent and specific inhibitor of protein phosphatases 1 and 2A. In cultured rat cortical neurons and a human neuroblastoma cell line (MSN), okadaic acid induces increased phosphorylation of MAP2 and tau concomitant with early changes in the neuronal cytoskeleton and ultimately leads to cell death. These results suggest that the diminished rate of MAP2 and tau dephosphorylation affects the stability of the neuronal cytoskeleton. The effect of okadaic acid was not restricted to neurons. Astrocytes stained with antibodies to glial fibrillary acidic protein (GFAP) showed increased GFAP staining and changes in astrocyte morphology from a flat shape to a stellate appearance with long processes.

Animals↗
PubMed1996

Effects of axonal injury on astrocyte proliferation and morphology in vitro: implications for astrogliosis.

Mechanisms inducing gliosis following injury in the central nervous sy stem are poorly understood. We evaluated the effect of axonal injury on astrocyte and Schwann cell proliferation and morphology in vitro. Purified rat dorsal root ganglion neurons grown on monolayers of rat neonatal cortical astrocytes (N-ASneonatal cultures) or sciatic nerve-derived Schwann cells (N-SC cultures) were mechanically injured. Non-injured cultures served as controls. Cell proliferation near lesions was monitored by autoradiography 1,2,4, and 8 days postinjury. Axonal injury caused a significant transient increase in astrocyte proliferation immediately proximal and distal to the lesion. The lesion did not induce marked changes in the intensity of glial fibrillary acidic protein (GFAP) immunoreactivity. However, processes from GFAP-positive cells usually arranged in random fashion in noninjured cultures were aligned perpendicularly to the cut distal to lesions. Ultrastructural analysis in lesioned N-ASneonatal cultures indicated that proximal to the lesion filament-filled astrocytes were intermingled with axons. Distal to the lesion astrocyte processes formed layers, between which an increased amount of collagen-like material appeared with time postlesion. Axons distal to the lesion degenerated by 2 days, coinciding with the early disappearance of neurofilament immunoreactivity. In noninjured and proximally in injured N-SC cultures, Schwann cells extended processes, engulfing some axons. Distal to the lesion, Schwann cells appeared more rounded and neurites remained until 4 days postinjury. Media conditioned by injured or non-injured N-ASneonatal cultures did not affect neuron-induced Schwann cell proliferation. These findings demonstrate that axonal injury and degeneration cause a transient increase in astrocyte proliferation and induce morphological changes in astrocytes consistent with the onset of gliosis.

Animals↗
PubMed1989

Protein phosphorylation in astrocytes mediated by protein kinase C: comparison with phosphorylation by cyclic AMP-dependent protein kinase.

The protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), has been found recently to transform cultured astrocytes from flat, polygonal cells into stellate-shaped, process-bearing cells. Studies were conducted to determine the effect of PMA on protein phosphorylation in astrocytes and to compare this pattern of phosphorylation with that elicited by dibutyryl cyclic AMP (dbcAMP), an activator of the cyclic AMP-dependent protein kinase which also affects astrocyte morphology. Exposure to PMA increased the amount of 32P incorporation into several phosphoproteins, including two cytosolic proteins with molecular weights of 30,000 (pI 5.5 and 5.7), an acidic 80,000 molecular weight protein (pI 4.5) present in both the cytosolic and membrane fractions, and two cytoskeletal proteins with molecular weights of 60,000 (pI 5.3) and 55,000 (pI 5.6), identified as vimentin and glial fibrillary acidic protein, respectively. Effects of PMA on protein phosphorylation were not observed in cells depleted of protein kinase C. In contrast to the effect observed with PMA, treatment with dbcAMP decreased the amount of 32P incorporation into the 80,000 protein. Like PMA, treatment with dbcAMP increased the 32P incorporation into the proteins with molecular weights of 60,000, 55,000 and 30,000, although the magnitude of this effect was different. The effect of dbcAMP on protein phosphorylation was still observed in cells depleted of protein kinase C. The results suggest that PMA, via the activation of protein kinase C, can alter the phosphorylation of a number of proteins in astrocytes, and some of these same phosphoproteins are also phosphorylated by the cyclic AMP-dependent mechanisms.

Animals↗
PubMed2004

Expression and cellular distribution of high- and low-affinity neurotrophin receptors in malformations of cortical development.

An increasing number of observations suggests an important and complex role for both high- (tyrosine kinase receptor, trk) and low- (p75) affinity neurotrophin receptors (NTRs) during development in human brain. In the present study, the cell-specific distribution of NTRs was studied in different developmental lesions, including focal cortical dysplasia (FCD, n = 15), ganglioglioma (GG, n = 15) and dysembryoplastic neuroepithelial tumors, (DNT, n = 10), from patients with medically intractable epilepsy. Lesional, perilesional, as well as normal brain regions were examined for the expression of trkA, trkB, trkC and p75(NTR) by immunocytochemistry. In normal postmortem human cortex, immunoreactivity (IR) for trk and p75(NTR) was mainly observed in pyramidal neurons, whereas no notable glial IR was found within the white matter. All three trk receptors were encountered in high levels in the neuronal component of the majority of FCD, GG and DNT specimens. Strong trkA, trkB and trkC IR was found in neurons of different size, including large dysplastic neurons and balloon cells in FCD cases. In contrast, p75(NTR) IR was observed in only a small number of neuronal cells, which also contain trk receptors. Glial cells with astrocytic morphology showed predominantly IR for trkA in FCD and GG specimens, whereas oligodendroglial-like cells in DNT showed predominently IR for trkB. P75(NTR) IR was observed in a population of cells of the microglial/macrophage lineage in both FCD and glioneuronal tumors. Taken together, our findings indicate that the neuronal and the glial components of malformations of cortical development express both high- and low-affinity NTRs. Further research is necessary to investigate how activation of these specific receptors could contribute to the development and the epileptogenicity of these developmental disorders.

Adolescent↗
PubMed1997

Compromised blood-nerve barrier, astrogliosis, and myelin disruption in optic nerves during fatal murine cerebral malaria.

We examined the optic nerve, as an analogous tissue to brain white matter, to assess possible relationships between changes in the blood-nerve barrier, axonal integrity, and astrocyte morphology in the central nervous system during fatal murine cerebral malaria (FMCM). In the FMCM model, namely, CBA mice infected with Plasmodium berghei ANKA, neurological symptoms begin around day 5 post-inoculation (p.i.) and mice become increasingly ill by day 7 p.i., at which time they lapse into coma and die. Using intravascular perfusion with horseradish peroxidase combined with light and electron microscopy, and GFAP immunohistochemistry, the optic nerves in malaria-infected mice were found to display i) breakdown of the blood-nerve barrier, detectable as early as day 3 p.i. (about 2 days before the onset of neurological symptoms) increasing to peak severity by day 7 p.i.; ii) monocytosis, vascular congestion, and monocyte adherence to the endothelium in the microvasculature during the later stages of the disease process; iii) an increased incidence of patchy axonal demyelination and degeneration, mostly associated with vascular changes and astrogliosis, beginning at day 5 p.i. and more evident by day 7 p.i.; and iv) an increased intensity of GFAP immunostaining, detectable from day 3 p.i. and peaking at day 7 p.i. These optic nerve changes were always seen in the infected individuals, though they varied in intensity. The temporal and anatomical coincidence between the compromised blood-nerve barrier, monocyte adherence to the vascular endothelium, astrocyte changes, neuronal degeneration, and demyelination in the optic nerve in FMCM suggests that these factors are mechanistically inter-related. These findings are consistent with the proposed immunopathological nature of FMCM and provide further evidence for the pivotal role of the CNS microvasculature in the disease process. This is the first investigation of involvement of the optic nerve in FMCM and the first demonstration, to our knowledge, of loss of axonal viability in this condition in any CNS tissue. The observed demyelination is consistent with reports by other workers on such changes in the brain in human cerebral malaria.

Animals↗
PubMed1985

The control of glial populations in brain: changes in astrocyte mitogenic and morphogenic factors in response to injury.

Injury to rat brain induces a 3-10-fold increase in the activity of factors capable of stimulating astrocyte DNA synthesis and cell division in vitro. Maximum mitogenic activity was reached 10-15 days post-lesion in both the tissue surrounding the wound and in the gelfoam filling the wound cavity. Factors capable of transforming the astrocyte morphology from polygonal-flat to fibrous-like (morphogens) could also be observed in brain tissue and showed increased activity beginning at 10 days postlesion. On the other hand, morphogenic activity was very low or absent in gelfoam extracts until 15 days postlesion. Both mitogenic and morphogenic factors were nondiffusible and were partly temperature and trypsin sensitive, i.e. they had the properties of protein-like substances, but seemed different from both epidermal and fibroblast growth factors. As judged by their filtration behavior on Amicon membranes, the molecular weight of mitogens and morphogens ranged from lower than 30,000 to greater than 100,000. Inhibitors of both mitogenic and morphogenic activities with molecular weight lower than 30,000 seemed to be also present in the brain extracts. The factors described here can account for the processes of astrocytosis and astrogliosis observed in vivo in response to CNS injury.

Animals↗
PubMed2006

Brain cytokine synthesis induced by an intraparenchymal injection of LPS is reduced in MCP-1-deficient mice prior to leucocyte recruitment.

We have previously shown that ischaemic lesions are smaller in monocyte chemoattractant protein-1-deficient (MCP-1(-/-)) mice than in wild-type (wt) controls. In addition to its role as a monocyte chemoattractant, monocyte chemoattractant protein-1 (MCP-1) has been proposed to contribute to lesion progression after focal ischaemia by driving local cytokine synthesis by resident glia. To investigate this hypothesis we injected lipopolysaccharide (LPS) into the brain parenchyma of MCP-1(-/-) mice and compared the resulting inflammatory response and production of proinflammatory cytokines to those in wt mice. Microglial and astrocyte morphological activation was the same in the two strains, but MCP-1(-/-) mice showed significantly lower levels of proinflammatory cytokine synthesis; interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) levels were up to 50% lower than in wt controls after 6 h. This reduced synthesis of proinflammatory cytokines occurred well before leucocyte recruitment to the central nervous system (CNS) is observed in this model of acute inflammation and thus cannot be attributed to lower numbers of recruited monocytes at the site of injury. We propose that MCP-1 contributes to acute CNS inflammation by pleiotropic mechanisms. In addition to being a potent chemoattractant for monocytes, we provide evidence here that MCP-1 can modify the responsiveness of CNS glia to acute inflammatory stimuli prior to leucocyte recruitment, thereby acting as a priming stimulus for cytokine synthesis in cells such as microglia.

Acute Disease↗
PubMed2001

Dose-dependent decrease in glial fibrillary acidic protein-immunoreactivity in rat cerebellum after lifelong ethanol consumption.

The effects of aging and lifelong ethanol consumption on astrocytic morphology and glial fibrillary acidic protein-immunoreactivity (GFAP-IR) in the cerebellar vermis obtained from ethanol-preferring Alko, Alcohol (AA) rats were analyzed by using computer-assisted image analysis. The ethanol-consuming animals (both male and female) were given ethanol (10%-12%, vol./vol.) as the only available fluid for 21 months (3-24 months), whereas the young (3 months) and the old (24 months) controls received water. In the male rats, but not in the female rats, an age-related decrease in GFAP-IR was found in folia II, VII, and X of the molecular layer, and in turn, an age-related increase was found in folium X of the granular layer, indicating opposite changes in GFAP-IR for male rats due to aging in adjacent brain regions. In the female rats, 21 months of daily average ethanol consumption of 6.6 g/kg resulted in decreased GFAP-IR in folium VII of the molecular layer, and the decrease in cerebellar GFAP-IR correlated with the average daily ethanol intake (r=-.886, P=.019) when folia II, IV, VII, and X were analyzed together. No effect of ethanol on GFAP-IR was detected in the granular layer or in the central white matter of the female rats. There was no change in GFAP-IR in any of the three cerebellar layers of the male rats with average daily ethanol consumption of 3.2 g/kg. These results indicate that the Bergmann glial fibers are the GFAP-expressing structures of the cerebellum most sensitive to moderate-to-heavy chronic ethanol exposure and that this effect is dose dependent.

Age Factors↗
PubMed2001

Gonadal steroids reduce the density of axospinous synapses in the developing rat arcuate nucleus: an electron microscopy analysis.

The developing brain is exquisitely sensitive to gonadal steroid hormones, which permanently differentiate the neural substrate during a critical developmental period. One of the more striking sexual dimorphisms in the adult rat brain is synaptic patterning in the arcuate nucleus (ARC); females have twice the number of axospinous synapses as males (Matsumoto and Arai [1980] Brain Res. 190:238-242). Previously, we have demonstrated that a similar dimorphism in spine densities on ARC dendrites is present as early as early as postnatal day 2 (PN2) in Golgi-impregnated rat brains (Mong et al. [1999] J. Neurosci. 19:1464-1472). Males have 37% fewer dendritic spines than females. Moreover, these spine densities are sensitive to changes in the hormonal milieu such that males castrated on the day of birth have a significant increase in spine density, whereas females masculinized at birth by gonadal steroid exposure have a decreased dendritic spine density. One of the limitations of the Golgi technique is the inability to confirm the presence of synapses. The current study used quantitative electron microscopy and demonstrated that testosterone exposure dramatically reduced axospinous synapses in the ARC by PN 2. Males had 54% fewer and masculinized females had 77% fewer axospinous synapses than females (P < 0.05 and P < 0.01, respectively). We previously reported that gonadal steroids induce coincident changes in neuronal and astrocyte morphology in the neonatal ARC (Mong et al., 1999), and here confirm that these changes include an altered synaptic pattern that is strikingly similar to that observed in the adult (Matsumoto and Arai, 1980).

Animals↗
PubMed1993

Further observations on Tau-positive glia in the brains with progressive supranuclear palsy.

The previously reported unusual, Tau-positive glia with astrocytic morphology seen in brain tissues from cases of progressive supranuclear palsy (PSP) were re-examined immunohistochemically using antibodies to CD44 and vimentin, as well as Alz-50. Four brains of PSP cases, one of whom had atypical clinical features, were examined. All four cases showed the unusual glia which were positive to Alz-50 and anti-CD44 antibodies, but negative to anti-vimentin antibody. Ultrastructurally, they had either paired nucleated or lobulated nuclei and the cytoplasm frequently contained lipofuscin pigment. The CD44 was located on the surface of the cell bodies and their processes. Such glia were most numerous in the striatum in all cases. They also appeared in the cortex and some subcortical nuclei in the three typical cases. They were not seen in the lower brain stem or cerebellum. In their morphological characteristics and regionally specific appearance, these unusual glia seemed similar to the Alzheimer type I glia which are commonly seen in hepatic encephalopathy or Wilson's disease.

Aged↗
PubMed1989

Prolonged survival and vascularization of xenografted human glioblastoma cells in the central nervous system of cyclosporine A treated rats.

Glioblastoma cells from three established lines were transplanted in oculo and in cerebrum to rat hosts. A very low dose of Cyclosporine A was found sufficient to allow graft survival whereas grafts in non-immunosuppressed animals did not survive. Moderate immunosuppression permitted long term graft survival without aggressive growth of glioblastoma cells, creating a protracted course during which neither cell rejection nor tumor proliferation occurred. A tumor reminiscent of a glioblastoma was only seen in one animal on high immunosuppression. Phenotypic changes such as the induction of glial fibrillary acidic protein (GFAP) production and an astrocytic morphology were observed in the cells growing in oculo but not in cerebrum. Vascularization was easily demonstrated with laminin immunofluorescence but the endothelial proliferation typical of glioblastomas was not seen.

Animals↗
PubMed1994

The engraftment of transplanted primary neuroepithelial cells within the postnatal mouse brain.

Primary neuroepithelial precursor cells carrying the reporter gene lacZ were transplanted into postnatal murine brain and assessed for their engraftment capacity. Freshly dissected precursors, derived from lacZ transgenic embryonic day 10 mouse brain, predominantly engrafted as discrete clusters, whereas the same precursors cultured in vitro with fibroblast growth factor-2, engrafted as single cells within the parenchyma of the hippocampus. Approximately 0.5% of the transplanted cells survived in the host brain for up to 3 months. Many of these cells displayed neuronal and astrocyte morphologies. These observations suggest that transplanted primary precursors derived from the embryonic brain can engraft and commit in situ to a variety of developmental fates.

Animals↗
PubMed2003

Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors.

The cell-specific distribution of multidrug resistance extrusion pumps was studied in developmental glioneuronal lesions, including focal cortical dysplasia (15 cases) and ganglioglioma (15 cases) from patients with medically intractable epilepsy. Lesional, perilesional, as well as normal brain regions were examined for the expression of the multidrug resistance gene 1 encoded P-glycoprotein (P-gp) and the multidrug resistance-associated protein 1 (MRP1) by immunocytochemistry. In normal brain MRP1 expression was below detection, whereas P-gp staining was present only in blood vessels. MRP1 and P-gp immunoreactivity was observed in dysplastic neurons of 11/15 cases of focal cortical dysplasia, as well as in the neuronal component of 14/15 ganglioglioma. Glial cells with astrocytic morphology within the lesion showed multidrug-resistant protein immunoreactivity (P-gp>MRP1). Moderate to strong MRP1 and P-gp immunoreactivity was observed in a population of large ballooned neuroglial cells. P-gp appeared to be most frequently expressed in glial fibrillary acidic protein-positive balloon cells (glial type), whereas MRP1 was more frequently expressed in microtubule-associated protein 2-positive balloon cells (neuronal type). In both types of lesions strong P-gp immunoreactivity was found in lesional vessels. Perilesional regions did not show increased staining in vessels or in neuronal cells compared with normal cortex. The predominant intralesional cell-specific distribution of multidrug transporter proteins supports the hypothesis of a constitutive overexpression as common mechanism underlying the intrinsic pharmaco-resistance to antiepileptic drugs of both malformative and neoplastic glioneuronal developmental lesions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1984

Factor VIII related antigen and glial fibrillary acidic protein immunoreactivity in the differential diagnosis of central nervous system hemangioblastomas.

Nineteen hemangioblastomas, nine angioblastic meningiomas, ten metastases to the brain (including five renal cell carcinomas), and five primary renal cell carcinomas were studied using the immunoperoxidase method for Factor VIII related antigen and glial fibrillary acidic protein (GFAP). All tumor types showed Factor VIII immunoreactivity confined to endothelial cells. Factor VIII immunostaining revealed a distinct, though probably nondiagnostic, vascular pattern for hemangioblastomas as compared with metastatic carcinomas and angioblastic meningiomas. Most of the hemangioblastomas and metastases showed numerous GFAP-reactive cells with unequivocal astrocytic morphology primarily at the interface with brain parenchyma but also occasionally deep within the tumor. Within metastases these cells often were associated with penetrating fibrovascular septa. In a minority of hemangioblastomas and metastatic carcinomas there were rare GFAP immunoreactive cells that were indistinguishable from stromal or metastatic tumor cells, respectively. Angioblastic meningiomas showed no GFAP reactivity. It is concluded that the presence of GFAP-reactive cells alone is not helpful in differentiating between hemangioblastomas and intra-axial lesions. The lack of stromal cell immunoreactivity in angioblastic meningiomas and the rare staining of stromal cells in hemangioblastomas, seen also in central nervous system (CNS) metastases, suggest that except for the endothelial cells lining vessels, these primary CNS lesions are not antigenically closely related to either endothelial cells or astroglia. Furthermore, in the evaluation of tumors within the CNS, the significance of rare GFAP-positive tumor cells must be interpreted with caution.

Cerebellar Neoplasms↗
PubMed1999

Primary CA1 and conditionally immortal MHP36 cell grafts restore conditional discrimination learning and recall in marmosets after excitotoxic lesions of the hippocampal CA1 field.

Common marmosets (Callithrix jacchus, n = 18) were trained to discriminate between rewarded and non-rewarded objects (simple discriminations, SDs) and to make conditional discriminations (CDs) when presented sequentially with two different pairs of identical objects signifying reward either in the right or left food well of the Wisconsin General Test Apparatus. After bilateral N-methyl-D-aspartate (0.12 M) lesions through the cornu ammonis-1 (CA1) field (7 microl in five sites), marmosets showed profound impairment in recall of CDs but not SDs, and were assigned to lesion only, lesion plus CA1 grafts and lesion plus Maudsley hippocampal cell line, clone 36 (MHP36) grafts groups matched for lesion-induced impairment. Cell suspension grafts (4 microl, 15-25 000 cells/microl) of cells dissected from the CA1 region of foetal brain at embryonic day 94-96, or of conditionally immortalized MHP36 cells, derived from the H-2Kb-tsA58 transgenic mouse neuroepithelium and labelled with [3H]thymidine, were infused at the lesion sites. The lesion plus MHP36 grafts group was injected five times per week with cyclosporin A (10 mg/kg) throughout testing. Lesion, grafted and intact control marmosets (n = 4-5/group) were tested on recall of SDs and CDs learned before lesioning and on acquisition of four new CDs over a 6-month period. Lesioned animals were highly impaired in recall and acquisition of CD tasks, but recall of SDs was not significantly disrupted. Both grafted groups of marmosets showed improvement to control level in recall of CDs. They were significantly slower in learning the first new CD task, but mastered the remaining tasks as efficiently as controls and were substantially superior to the lesion-only group. Visualized by Nissl staining, foetal grafts formed clumps of pyramidal-like cells within the denervated CA1 field, or jutted into the lateral ventricles. MHP36 cells, identified by beta-galactosidase staining and autoradiography, showed neuronal and astrocytic morphology, and were distributed evenly throughout the CA1 region. The results indicate that MHP36 cell grafts are as functionally effective as foetal grafts and appear to integrate into the host brain in a structurally appropriate manner, showing the capacity to differentiate into both mature neurons and glia, and to develop morphologies appropriate to the site of migration. These findings, which parallel the facilitative effects of foetal and MHP36 grafts in rats with ischaemic CA1 damage, offer encouragement for the development of conditionally immortal neuroepithelial stem cell lines for grafting in conditions of severe amnesia and hippocampal damage following recovery from cardiac arrest or other global ischaemic episodes.

Animals↗