Hippocampal Grafts Research Articles

Fetal hippocampal transplants attenuate CA3 pyramidal cell death resulting from fluid percussion brain injury in the rat.

Transplantation of fetal neural tissue has been demonstrated to prevent neuronal loss in a number of CNS injury models including spinal cord contusion. However, no studies have examined the neuroprotective role of fetal transplants in models of traumatic brain injury. The present study examined the ability of fetal neural grafts to attenuate neuronal loss resulting from lateral fluid percussion (FP) brain injury in the rat. Lateral FP in the rat elicits a focal contusion within the parietal/temporal cortex and induces cell death in a subset of hippocampal CA3 pyramidal neurons. To examine potential neuroprotective effects of fetal neural grafts, either E16 fetal hippocampus, E16 fetal cortex, or sterile lactated Ringers was stereotaxically transplanted directly into contused cortex 2 days after FP brain injury. The effects of fetal transplants upon adjacent injured hippocampal CA3 regions were then assessed at 4 weeks after grafting utilizing quantitative image analysis. Both fetal cortex and hippocampal grafts survived within contused cortex. Fetal hippocampal grafts significantly attenuated CA3 cell death resulting from lateral fluid percussion, while fetal cortical transplants induced a small, but nonsignificant, amelioration of CA3 pyramidal loss. Thus, neuroprotection by fetal grafts appeared to be tissue specific with hippocampal, but not cortical, fetal transplants significantly reducing posttraumatic CA3 loss. In summary, fetal neural transplantation can ameliorate hippocampal cell death following experimental brain injury.

C-JUN, KROX-24, and c-FOS Expression in Hippocampal Grafts Placed in Excitotoxic Hippocampal Lesions of the Rat

Hippocampal transplants were examined for the expression of three specific immediate early gene encoded proteins in order to establish if grafted immature tissue maintains the basic molecular program necessary for gene transcription after grafting to excitotoxic (ibotenic acid-induced) lesions in adult host rat brains. The transplants were derived from newborn donor rats and were analyzed immunocytochemically for the presence of c-JUN, KROX-24, and c-FOS transcription factors 5 months after grafting. The expression and distribution patterns of these genes in the host hippocampus were identical to those in hippocampal neurons of normal untreated animals. c-JUN-, KROX-24-, and c-FOS-labeled neurons were also present in the transplants, where KROX-24 and c-FOS exhibited a distribution similar to host hippocampus. In contrast, c-JUN was more extensively expressed in the transplants, suggesting a molecular response to the grafting conditions and the actual graft-host brain interactions.

Selective laser-activated lesioning of prelabeled fetal hippocampal grafts by intracellular photolytic chromophore.

Selective removal of grafted tissue is critical to assess the functional role of that tissue in the host, yet is technically difficult for well-dispersed neural grafts. We labeled fetal hippocampal cells with both a nuclear marker (5'-bromodeoxyuridine) and a cytoplasmic marker (latex microspheres) before grafting into normal adult hippocampus. A nontoxic chromophore, chlorin e6, was conjugated on to the surface of latex microspheres of the treatment group. Chlorin e6 produces cytotoxic singlet oxygen only during photoactivation. Grafted animals received transcranial exposure to various intensities of near-infrared laser light. Following laser exposure, grafts were observed in all groups except in transplants prelabeled with chlorin e6 latex microspheres. An optimal laser exposure of 50-100 J/cm2 (4-8 min) was found to selectively remove only the chlorin e6-containing grafted cells. With increasing doses of laser illumination, non-specific lesions of the host tissue surrounding the graft were induced. Quantitative graft analysis, in the absence of laser exposure, indicated that the survival of grafted cells was similar between control transplants labeled with latex microspheres alone and grafts labeled with latex microspheres plus chlorin e6. This is further evidence that chlorin e6 by itself was not toxic without laser exposure. The results clearly demonstrate that singlet oxygen-induced cell photolysis can result in selective, non-invasive removal of dispersed grafted cells located in adult hippocampus. This technique may facilitate defining specific mechanisms of action of grafted cells which mediate functional recovery in different host conditions.

Alterations in α-adrenoceptors in aging intraocular hippocampal grafts

Age-related changes of hippocampal α 1- and α 2-adrenoceptors were investigated using intraocular hippocampal transplants combined with 3H-prazocin and 3H-para-aminoclonidine ( 3H-PAC) autoradiography. Young hippocampal grafts in young hosts and old grafts in old hosts innervated by noradrenergic sympathetic fibers were studied. In addition, young and old hippocampal grafts were examined following noradrenergic denervation by superior cervical ganglion removal. The 3H-PAC binding was significantly reduced in aged grafts as compared to young grafts whereas the 3H-prazocin binding did not change with age. After sympathetic denervation, both 3H-PAC and 3H-prazocin binding increased significantly in young grafts. In aged adrenergically denervated grafts, α 2-receptor binding was again significantly reduced whereas α 1-receptor binding was not significantly different from that in young denervated grafts. Taken together, these results indicate a selective age-related reduction in hippocampal postsynaptic α 2-receptors which is intrinsically determined.

Integration of hippocampal suspension grafts with host neocortex

The possibility of histological and functional integration of nervous tissue heterotopically grafted into the adult host brain was investigated. Suspensions of embryonic (E17-18) rat hippocampus with dentate fascia were placed into acute cavities in the barrel field of young adult rats (n = 25). Golgi-Cox silver impregnation and Cresyl Violet stain were used for histological analysis 3-4 months postgrafting. The surviving grafts were present in 80% of the grafted animals. Only three out of 20 surviving grafts were completely isolated from the surrounding host brain; other grafts had areas of direct confluence with the host neuropil. Extracellular recording of neuronal activity revealed normal spontaneous activity typical of the hippocampus in the majority of the grafts. Electrical stimulation of the posterior nucleus of the thalamus, homolateral motor neocortex, contralateral barrel field, and sensory stimulation of the host evoked responses in 50-60% of the grafted neurons. This did not differ significantly from the responsiveness of the similarly tested neurons of homotopic neocortical suspension grafts. The latencies of the responses in the hippocampal grafts were consistently longer (by about 10 ms) than in the neocortical ones. Comparison of the hippocampal suspension grafts with other types of hippocampal and neocortical grafts suggests that under certain conditions heterotopic tissue can be successfully integrated into the host brain. Development of the host-graft interconnections depends on topical proximity, the presence of denervated synaptic loci in both tissues, elimination of the intragraft neuronal targets and disruption of the intrinsic connections between them.

Hypothalamic tissue stimulates hippocampal pyramidal neuron survival during development: Evidence from intraocular double transplants

The present study was undertaken to evaluate innervation and possible growth promotion by posterior hypothalamic tissue on different areas that are, or are not, interactive with this brain region during development. Posterolateral hypothalamus was dissected from embryonic day 17 rat fetuses, and inserted into the anterior chamber of the eye of adult rat hosts. Two weeks postgrafting, a second transplant consisting of either fetal hippocampal, cerebellar, or lung tissue was placed adjacent to the first graft. Growth of the intraocular double transplants was monitored weekly by measurements through the cornea. Fetal hippocampal tissue grew significantly larger when placed together with a hypothalamic graft, as compared to single hippocampal transplants. Cerebellar or lung tissue growth was not stimulated by a hypothalamic cograft. Pyramidal neuron cell counts demonstrated a significantly higher final number of these neurons in growth-stimulated hippocampal grafts, as compared to non-stimulated single hippocampal grafts. Immunohistochemistry with antibodies directed against histamine or histidine decarboxylase revealed that hippocampal transplants received the most dense histaminergic innervation. Cerebellar transplants contained occasional histaminergic neurites, and lung tissue never exhibited any histaminergic innervation from the adjacent hypothalamic graft. Taken together, these results demonstrate a growth-promoting effect of posterior hypothalamic tissue on developing hippocampal tissue, as well as target specificity of histaminergic innervation patterns.

Synapsin I in intraocular hippocampal transplants during maturation and aging: Effects of brainstem cografts

The role of target innervation for maintenance of synaptic proteins in the hippocampal formation during aging was investigated. Fetal CA1 tissue and brainstem tissue containing the nucleus locus coeruleus was dissected from albino rats and grafted sequentially into the anterior chamber of the eye of adult rat recipients. Synapsin protein distribution and levels were evaluated by immunohistochemistry and quantitative immunolabeling in single hippocampal grafts or brainstem-hippocampal double grafts at 6, 12, or 24 mo postgrafting. The synapsin levels in 6-mo-old single hippo-campal transplants were significantly lower than those in situ, and remained at these lower levels at 12 and 24 mo. On the contrary, synapsin levels were close to normal in the hippo-campal portion of double grafts in the 6- and the 12-mo-group. However, in the 24-mo-old double transplants the levels had declined significantly, approaching levels seen in single hippocampal grafts. The immunoblot results were supported by morphological observations with synapsin antibodies and immunohistochemistry. The present data demonstrate that hippocampal tissue maintained near normal synapsin levels when grafted together with brainstem tissue, as compared to the lower levels seen in single hippocampal grafts. This normalization of synapsin levels was, however, not seen in the aged hippocampal-brainstem double grafts.

Synapsin I in intraocular hippocampal transplants during maturation and aging: effects of brainstem cografts.

The role of target innervation for maintenance of synaptic proteins in the hippocampal formation during aging was investigated. Fetal CA1 tissue and brainstem tissue containing the nucleus locus coeruleus was dissected from albino rats and grafted sequentially into the anterior chamber of the eye of adult rat recipients. Synapsin protein distribution and levels were evaluated by immunohistochemistry and quantitative immunolabeling in single hippocampal grafts or brainstem-hippocampal double grafts at 6, 12, or 24 mo postgrafting. The synapsin levels in 6-mo-old single hippocampal transplants were significantly lower than those in situ, and remained at these lower levels at 12 and 24 mo. On the contrary, synapsin levels were close to normal in the hippocampal portion of double grafts in the 6- and the 12-mo-group. However, in the 24-mo-old double transplants the levels had declined significantly, approaching levels seen in single hippocampal grafts. The immunoblot results were supported by morphological observations with synapsin antibodies and immunohistochemistry. The present data demonstrate that hippocampal tissue maintained near normal synapsin levels when grafted together with brainstem tissue, as compared to the lower levels seen in single hippocampal grafts. This normalization of synapsin levels was, however, not seen in the aged hippocampal-brainstem double grafts.

Mutual interaction between host and graft tissues in embryonic neural transplantation.

The differentiation of AChE-positive cells in embryonic neural grafts from various brain regions into the hippocampus after fimbria-fornix transection was investigated. Rat fetal cell suspensions of basal forebrain, hippocampus, mesencephalon or cortex were prepared from fetuses of either embryonic day 14 (E14) or day 19 (E19) gestational age, and these were transplanted into the rat brain after unilateral fimbria-fornix transection. Dense acetylcholinesterase (AChE) positive fibres were observed in both E14 and E19 basal forebrain grafts. These fibres were also found in E14 hippocampal grafts. However E19 hippocampal grafts did not have any AChE-positive fibres. These results suggest that E14 hippocampal grafts might be affected by the host brain tissues and differentiate into cholinergic neurones.

Fetal transplants in rat hippocampus following kainic acid lesions: influence of post-lesion delay on graft survival and integration

Host brain receptivity to fetal hippocampal grafts was investigated following transplantation into unilateral kainic acid (KA) lesions of adult rat hippocampus. E18-E19 hippocampal cell suspensions were labeled with rhodamine dextran amine and transplanted bilaterally into hosts at various times following the KA-lesion. After one to three and one half months survival the grafts (contained within host hippocampal slices) were analyzed using intracellular electrophysiological techniques. A nonparametric graft index was developed which assessed the overall size and distribution of the graft. Using this grading system graft development was noted to be significantly enhanced for grafts placed into hosts with KA lesions at either 2-4 days or 11-12 days following the lesion, compared to grafts placed at either 6-7 days or 27-33 days after the lesion. Also, grafts implanted at delays of either 14-16 or 28-33 days appeared to have fewer surviving cells but were more dispersed within the host brain than grafts at shorter post-lesion implant times. Synaptic responses to host stimulation were noted in most grafts. Intracellular staining of transplanted neurons showed considerable development of cell processes but atypical pyramidal cell morphology and ectopic location; numerous axons traveled into the host tissue. The time course of lesion-induced host receptivity appeared to significantly influence graft development and maturation. In this study graft survival was partially independent from cell migration. This differential effect may be due to various aspects of host brain receptivity, which in turn is influenced by the delay between the host brain lesion and grafting.

Influence of fetal hippocampal grafts on lesions induced by intraventricular infusion of N-methyl-D-aspartate (NMDA) into rats

Effects of fetal hippocampal transplants were evaluated following a prolonged intraventricular excitotoxic lesion (1.0 mg of N-methyl-D-aspartate over two weeks infusion) in F344 rats. The septum and ipsilateral hippocampus (CA1 and dentate regions) showed extensive cell loss, decreased acquisition of spatial memory was observed and a decrease in AChE positive fiber innervation to the hippocampus was noted following the lesion. Fetal hippocampal transplants into the posterior lateral ventricle resulted in moderate graft survival and physiological analysis of graft-host interconnection in vitro demonstrated evoked field potentials. However, the transplants did not lead to significant improvement in behavior, possibly due to poor synaptic integration of the intraventricular transplants into the host hippocampus. The prolonged intraventricular NMDA lesion may be helpful to understand a mixed lesion model of both septal areas and hippocampus and also as a background lesion in which to assess the connectivity and development of various types of neural grafts.

Long axon growth from embryonic neurons transplanted into myelinated tracts of the adult rat spinal cord

Suspensions of embryonic mouse hippocampal neurons were micro-transplated into the high cervical region of the corticospinal tracts and the ascending dorsal columns of immunosuppressed adult rat hosts. The mouse specific marker, M6, showed that the transplanted neurons grew long, straight, and uniform axons which passed both rostrally and caudally in a narrow beam within the tract occupied by the transplant. The donor axons did not fasciculate with each other, but were intermingled singly with the host myelinated axons, parallel to them and to the host interfascicular glial rows. The donor axons extended at about 0.5 mm per day for the first 6–10 days, after which they slowed down, gradually reaching a maximum distance of around 8 mm from the grafts by 6–7 weeks. Beyond this time M6 ceased to be an effective marker. The presence of the donor axonal projections was confirmed by retrograde cellular labelling of the donor cells from injections of horseradish peroxidase caudal to the transplants in the same host tract. To test whether the donor embryonic hippocampal axons would be attracted to neuropil containing appropriate postsynaptic sites, embryonic rat hippocampal grafts were placed caudal to the mouse grafts. When placed where they could make direct contact with the projection, the rat grafts became M6 positive, suggesting that they had been innervated by mouse axons. But even when placed directly within the beam of donor projections, the rat grafts did not prevent large numbers of mouse axons from continuing caudally in the host spinal tracts. When the rat grafts were placed to one side of the beam of donor projection, the long projecting mouse axons did not deviate from their course. Thus the long ascending and descending myelinated fibre tracts of the adult spinal cord provide a permissive environment for the rapid growth of axons from embryonic donor neurons from a region not normally projecting to the spinal cord. The route taken by these axons is determined by the internal structure of the host tracts. Donor interfascicular axons are able to pass, without deviation, through or beside tissue containing appropriately matched postsynaptic targets.

The ontogeny of estrogen receptors in heterochronic hippocampal and neocortical transplants demonstrates an intrinsic developmental program

We investigated the intrinsic vs. environmental regulation of estrogen receptor (ER) ontogeny in the neocortex, hippocampus and hypothalamus by employing a heterochronic transplantation paradigm. These studies were based on previous reports demonstrating that neural ER develop asynchronously with quantitatively distinct ontogenetic profiles in various brain regions. Fetal (E14–15) hippocampal, frontal cortical or hypothalamic preoptic area (HPOA) primordial tissue was grafted into frontal cortical lesion cavities made in newborn (PND-0) rats. Thus, the grafted tissue was 1 week younger than the host. Two and 4 weeks following transplantation surgery, which corresponds to a theoretical donor age of PND-7 and PND-21, the grafts, a region of the host neocortex surrounding the transplant, and the host hippocampus, frontal cortex or HPOA (depending on graft type) were assayed for ER content using in vitro binding assays. ER concentration in hippocampal grafts at theoretical age PND-7 were significantly higher than those found in the host (PND-14) hippocampus and in the host neocortex adjacent to the transplant. By theoretical graft age PND-21, ER concentration in hippocampal transplants had decreased to levels comparable to those found in the host. This developmental pattern is analogous to that previously reported for the in situ hippocampus. A similar profile of ER concentration corresponding to the donor age developmental timetable was observed in neocortical grafts. ER levels in HPOA grafts did not change from theoretical donor age PND-7 to PND-21, which also corresponds to the normal ontogenetic profile. These data suggest that region-specific developmental patterns of ER expression in the rat brain are specified by embryonic day 14.

Neural grafting to ischemic CA1 lesions in the rat hippocampus: An autoradiographic study

Fetal hippocampal neurons were stereotaxically transplanted to five-day-old ischemic CA1 lesions in adult rat hippocampi. The recipient brains were examined 14 or 100 days later. The grafts survived well, and transplanted cells usually formed clusters in the host CA1 subfield. In vitro receptor autoradiography was employed to map the following receptors, the ligands indicated in parentheses being used for labeling: muscarinic cholinergic ([ 3H]quinuclidinyl benzilate), adenosine A 1 ([ 3H]cyclohexyladenosine), kainate ([ 3H]kainic acid), spirodecanone ([ 3H]spiperone), opioid ([ 3H]naloxone), and GABA A ([ 3H]muscimol). The receptor autoradiographic technique showed significant binding of the six ligands in all hippocampal grafts two weeks after transplantation. One hundred days following transplantation, almost all receptors, especially muscarinic cholinergic, adenosine A 1 and opioid receptor bindings in grafts, had significantly increased compared to bindings two weeks after transplantation. At this time, kainate and muscarinic cholinergic receptors in grafts had increased up to the near normal level of the CA1 in the hippocampus. Interestingly, adenosine A 1 receptors in the grafted side had significantly increased not only in the CA1 but also in the stratum oriens of the CA3 compared with that in the non-grafted side. The increase of [ 3H]quinuclidinyl benzilate binding corresponded well with the innervation of acetylcholinesterase-positive fibers at 100 days after grafting. These results demonstrate that the transplanted neurons, which showed both pre- and post-synaptic autoradiographic markers in the ischemic CA1 lesions, are able to develop their properties and express the nature of normal hippocampal neurons.

Amelioration of memory deficits by intraperitoneal injections of substance P in rats with hippocampal lesions and grafts of fetal nervous tissue

Amelioration of memory deficits by intraperitoneal injections of substance P in rats with hippocampal lesions and grafts of fetal nervous tissue

Differential effects of platelet-derived growth factors on fetal hippocampal and cortical grafts: Evidence from intraocular transplantation in rats

Effects of platelet-derived growth factor-AA (PDGF-AA) and platelet-derived growth factor-BB (PDGF-BB) on developing parietal cortex (E16) and hippocampal (E18–E19) grafts were studied using the in vivo method of intraocular transplantation. Survival and growth of grafts in the anterior eye chamber of adult host rats under the influence of regular treatments with 0.5 ng (in a 100 ng/ml concentration) PDGF-AA or PDGF-BB was followed and compared to those receiving vehicle solution alone (0.5 mg HSA/ml Hanks). Both PDGF-AA and PDGF-BB increased the volume of transplanted cortical grafts. PDGF-BB also exerted trophic effects on grafted hippocampal tissue whereas PDGF-AA seemed to inhibit hippocampal growth. Histological and immunohistochemical studies revealed an increase in the density of astroglial elements in PDGF-AA- and PDGF-BB-treated cortical grafts whereas the PDGF-AA- and PDGF-BB-treated hippocampal grafts maintained a cytoarchitecture closely resembling that of control grafts. These findings support in vitro experiments showing that developing glial cells are stimulated by PDGFs and we further propose regional differences of action of PDGFs in the developing central nervous system.

Hippocampal grafts into the intact brain induce epileptic patterns

Spontaneous hippocampal EEG activity and evoked field potentials were investigated in intact rats and in animals with fetal hippocampal grafts. Pieces of hippocampal grafts, derived from 15- to 16-day-old fetuses, were used to prepare cell suspensions and grafted directly into the intact hippocampus. Control animals received suspension grafts of the cerebellum derived from fetuses of identical age. Host hippocampal electrical patterns were monitored with chronic single electrodes or with a 16-microelectrode probe from 7 to 10 months after grafting. In contrast to previously reported high survival rates of fetal grafts in studies with damage to the host brain prior to grafting, survival of both hippocampal (60%) and cerebellar grafts (20%) was very poor in the intact hippocampus. In animals with cerebellar transplants or without surviving grafted neurons the electrical activity of the host hippocampus was indistinguishable from normal controls. In rats with hippocampal grafts short duration, large amplitude EEG spikes (up to 10 mV) were recorded, predominantly during immobility. When the EEG spikes (putative interictal spikes) were of large amplitude and contained population spikes, test evoked responses delivered to the perforant path were suppressed after the spontaneous events. In contrast, evoked responses were facilitated by interictal spikes without population spikes. The threshold of electrically induced afterdischarges did not differ significantly between groups of intact rats and animals with or without hippocampal grafts. However, in three rats with hippocampal grafts the evoked afterdischarges were associated with behavioral seizures. In two of these rats spontaneously occurring seizures were also observed. Synaptophysin-immunoreactivity demonstrated growth of the host mossy fibers into the graft.(ABSTRACT TRUNCATED AT 250 WORDS)

Early neural grafts transiently reduce the behavioral effects of radiation-induced fascia dentata granule cell hypoplasia

X-irradiation of the neonatal rat hippocampus produces a selective hypoplasia of fascia dentata granule cells, locomotor hyperactivity, perseverative movements and deficits in passive avoidance. We previously reported that transplantation of fetal hippocampal tissue into the adult (age= 182 ± 4days) brain produced a partial recovery of these behavioral deficits. Since graft/host interconnections are more prominent when transplants are conducted soon after radiation-induced hippocampal damage, in this study we transplanted hippocampal or cerebral cortex neurons when host rats were33 ± 5days of age (i.e. only 10 days after radiogenic brain damage). Behavioral evaluations were conducted 80 and 182 days after transplantation or surgical control procedures. In the first test series only, selective components of locomotion (e.g. stereotypy and total distance traveled) and perseverative turning (e.g. mean bout length and turning speed topography) were normalized by the hippocampal grafts. Radiation-induced changes in passive avoidance wereless prominent in these studies than in past experiments. Still, transplantation of hippocampal tissue improved performance on this learning task as well. Cerebral cortex grafts did not produce reliable improvements in most behavioral measures. These data suggest that hippocampal grafts placed soon after X-ray induced fascia dentata hypoplasia reduce a broad range of behavioral deficits. However, these benefits are transient and, for the most part, depend on the use of transplant tissues homologous with those damaged.

The effects of cholinergic drugs and cholinergic-rich foetal neural transplants on alcohol-induced deficits in radial maze performance in rats

Chronic alcohol (20% v/v in drinking water for 28 weeks) impaired acquisition of radial maze spatial and associative tasks by increasing both within-trial working and long-term reference memory errors; animals with high (above the median of 100 mg/100 ml) blood alcohol concentrations (BACs) during treatment were significantly more impaired than those with BACs below the median. Alcohol-treated rats showed improvements in radial maze performance after treatment with cholinergic agonists (arecoline and nicotine) and disruption with antagonists (scopolamine and mecamylamine) at low doses which did not affect controls. These effects were more pronounced for working than reference memory, and not manifest with the peripherally acting antagonists hexamethonium and N-methylscopolamine. Transplants into cortex and hippocampus of cholinergic-rich basal forebrain (BF) and ventral mesencephalon (VM) foetal neural tissue improved radial maze performance of alcohol-treated rats to control level over a period of 9-12 weeks after grafting. Cholinergic-poor foetal hippocampal (HC) grafts were without effect. BF and VM, but not HC, grafts showed dense acetylcholinesterase (AChE) staining, tyrosine-hydroxylase staining was most pronounced in VM sections and dopamine-beta-hydroxylase staining was minimal in all grafts. Choline acetyltransferase (ChAT) activity was significantly reduced in cortex and hippocampus of alcohol-treated rats, except those given cholinergic-rich transplants. Alcohol treatment also significantly reduced AChE-positive cell counts in the nucleus basalis, medial septal and diagonal band brain areas, at the sources of the forebrain cholinergic projection system (FCPS). Cortical levels of noradrenaline were significantly reduced in all alcohol-treated rats, regardless of transplant, whereas cortical dopamine content was significantly elevated in all rats receiving transplants, regardless of behavioural effect, but not in alcohol-treated controls. Forebrain serotonin levels were not significantly altered by grafting or alcohol treatment. These results suggest that damage to the FCPS, as shown by reduced ChAT activity in target areas, and reduced AChE cell counts in projection areas, played an important part in the radial maze deficits displayed by alcohol-treated rats, since these animals were sensitive to cholinergic drug challenge, and cholinergic-rich transplants from two different sites in foetal brain elevated ChAT activity and restored cognitive function. In contrast alcohol- or graft-induced alterations in other transmitter systems did not correlate with the pattern of behavioural deficit and recovery.

Transplants of mouse trisomy 16 hippocampus provide a model of Alzheimer's disease neuropathology.

Alzheimer's disease, which is characterized by amyloid plaques and neurofibrillary tangles, may be attributed to the abnormal expression of gene(s) located on human chromosome 21. Genetic linkage studies have narrowed the region of candidate genes to 21q11.2-21q22 of the long arm of this chromosome. Several single copy sequences within this region, including the amyloid precursor protein (APP), have been mapped to mouse chromosome 16. Reliable strategies exist for breeding Trisomy 16 mice. However, the consequences of developmental overexpression of genes on chromosome 16 have not been previously investigated, because of the lethal effects of this aneuploidy during gestation. In the present report, we employ neural transplantation to study long-term survival and pathogenesis in Trisomy 16 central nervous system tissues. Immunocytochemical staining with antiserum raised against the synthetic APP, beta-A4 and alpha 1-antichymotrypsin revealed numerous densely stained cells within hippocampal grafts of Trisomy 16 mice. Similarly, a population of grafted cells were positively stained following incubation with an antiserum raised against components of the pathological neurofibrillary tangle and with the monoclonal antibodies Tau 6.423 and ubiquitin.