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B J Hoffer

Publications and source records attributed to B J Hoffer.

At least 73 records · Page 4Linked to original sources
PubMed1995

Morphological and functional effects of intranigrally administered GDNF in normal rhesus monkeys.

Effects of a single injection of either 150 micrograms human recombinant glial cell line-derived neurotrophic factor (rGDNF) or vehicle into the right substantia nigra were analyzed in 12 normal adult female rhesus monkeys. The studies included evaluating whole animal behavior, electrochemical recordings of striatal dopamine release, neurochemical determinations of basal ganglia and nigral monoamine levels, and immunohistochemical staining of the nigrostriatal dopamine system. The behavioral effects over the 3-week observation period following trophic factor administration were small, with blinded observers unable to distinguish between GDNF- and vehicle-treated animals. Quantitative measurements did show that five of six trophic factor recipients experienced some weight loss and four of the six GDNF recipients displayed small, but significant, increases in daytime activity levels. In vivo electrochemical recordings in the ipsilateral caudate and putamen 3 weeks after GDNF administration revealed increased potassium-evoked release of dopamine in trophic factor recipients. In a second series of animals killed at the same time, dopamine levels in the substantia nigra and ventral tegmental area of GDNF recipients were significantly increased, with ipsilateral values more than 200% higher than contralateral and control levels. Levels of the dopamine metabolite HVA were significantly elevated in the substantia nigra, ventral tegmental area, and caudate nucleus ipsilateral to the trophic factor injection. There was a trend toward increased HVA levels in the ipsilateral putamen, nucleus accumbens, and globus pallidus in GDNF-treated animals, but the ratios of HVA to dopamine were not significantly different between vehicle- and GDNF-treated recipients. Although some tissue damage from the delivery of concentrated trophic factor was evident, dopamine neurons remained in an adjacent to the injection site. In the substantia nigra ipsilateral to GDNF administration, dopamine-neuron perikaryal size was significantly increased, along with a significant increase in tyrosine hydroxylase-positive axons and dendrites. We conclude that, in the adult rhesus monkey, a single intranigral GDNF injection induces a significant upregulation of mesencephalic dopamine neurons which lasts for weeks.

Animals↗
PubMed1995

Retrograde axonal transport of glial cell line-derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult.

The recently cloned, distant member of the transforming growth factor beta (TGF-beta) family, glial cell line-derived neurotrophic factor (GDNF), has potent trophic actions on fetal mesencephalic dopamine neurons. GDNF also has protective and restorative activity on adult mesencephalic dopaminergic neurons and potently protects motoneurons from axotomy-induced cell death. However, evidence for a role for endogenous GDNF as a target-derived trophic factor in adult midbrain dopaminergic circuits requires documentation of specific transport from the sites of synthesis in the target areas to the nerve cell bodies themselves. Here, we demonstrate that GDNF is retrogradely transported by mesencephalic dopamine neurons of the nigrostriatal pathway. The pattern of retrograde transport following intrastriatal injections indicates that there may be subpopulations of neurons that are GDNF responsive. Retrograde axonal transport of biologically active 125I-labeled GDNF was inhibited by an excess of unlabeled GDNF but not by an excess of cytochrome c. Specificity was further documented by demonstrating that another TGF-beta family member, TGF-beta 1, did not appear to affect retrograde transport. Retrograde transport was also demonstrated by immunohistochemistry by using intrastriatal injections of unlabeled GDNF. GDNF immunoreactivity was found specifically in dopamine nerve cell bodies of the substantia nigra pars compacta distributed in granules in the soma and proximal dendrites. Our data implicate a specific receptor-mediated uptake mechanism operating in the adult. Taken together, the present findings suggest that GDNF acts endogenously as a target-derived physiological survival/maintenance factor for dopaminergic neurons.

Animals↗
PubMed1995

Allogeneic grafts of fetal dopamine neurons: immunological reactions following active and adoptive immunizations.

To define the importance of adoptive sensitization and duration of graft residence on transplant alloimmunization, behavioral and histochemical parameters were examined in unilaterally 6-OHDA-lesioned F344 rat hosts which received fetal ventral mesencephalic (VM) grafts from Wistar-Furth (WF) donors. In all animals which showed increased rotations after alloimmunization, increased numbers of T cell receptor (TcR) positive, CD8+ lymphocytes were detected in the grafts. In addition, an increased density of class I MHC antigens was seen in the graft and in the adjacent host brain. Lesser numbers of CD4+, CD11b+, and MHCII+ positive elements were also seen. Perivascular cuffing was often found in actively immunized animals. An increase in TcR+ and MHC class I+ elements was also seen in animals only adoptively immunized. The tyrosine hydroxylase positive graft area was also markedly reduced in actively immunized animals and the extent of reduction correlated with the number of cells used for immunization. These studies indicate that established allografts can evade rejection as long as host lymphocytes are not activated against graft alloantigens. In addition, increasing graft residence time in the host and adoptive immunization render the graft more susceptible to subsequent rejection.

Animals↗
PubMed1995

Glial cell line-derived neurotrophic factor supports survival of injured midbrain dopaminergic neurons.

Glial cell-lined derived neurotrophic factor (GDNF) has been shown to promote survival of developing mesencephalic dopaminergic neurons in vitro. In order to determine if there is a positive effect of GDNF on injured adult midbrain dopaminergic neurons in situ, we have carried out experiments in which a single dose of GDNF was injected into the substantia nigra following a unilateral lesion of the nigrostriatal system. Rats were unilaterally lesioned by a single stereotaxic injection of 6-hydroxydopamine (6-OHDA; 9 micrograms/4 microliters normal saline with 0.02% ascorbate) into the medial forebrain bundle and tested weekly for apomorphine-induced (0.05 mg/kg s.c.) contralateral rotation behavior. Rats that manifested > 300 turns/hour received a nigral injection of 100 micrograms GDNF, or cytochrome C as a control, 4 weeks following the 6-OHDA lesion. Rotation behavior was quantified weekly for 5 weeks after GDNF. Rats were subsequently anesthetized, transcardially perfused, and processed for tyrosine hydroxylase immunohistochemistry. It was found that 100 micrograms GDNF decreased apomorphine-induced rotational behavior by more than 85%. Immunohistochemical studies revealed that tyrosine hydroxylase immunoreactivity was equally reduced in the striatum ipsilateral to the lesion in both cytochrome C and GDNF-injected animals. In contrast, large increments in tyrosine hydroxylase immunoreactivity were observed in the substantia nigra of animals treated with 100 micrograms of GDNF, with a significant increase in numbers of tyrosine hydroxylase-immunoreactive cell bodies and neurites as well as a small increase in the cell body area of these neurons. The results suggest that GDNF can maintain the dopaminergic neuronal phenotype in a number of nigral neurons following a unilateral nigrostriatal lesion in the rat.

Animals↗
PubMed1995

Glial cell line-derived neurotrophic factor stimulates fiber formation and survival in cultured neurons from peripheral autonomic ganglia.

Human recombinant glial cell line-derived neurotrophic factor (GDNF) was tested for its ability to stimulate fiber formation and neuron survival in primary cultures of peripheral ganglia dissected from the chicken embryo. GDNF, first characterized by its actions on central nervous system (CNS) neurons, had a marked stimulatory effect on fiber outgrowth in sympathetic and ciliary ganglia. Weaker responses were evoked in sensory spinal and nodose ganglia and in the ganglion of Remak. In addition, survival of neurons from the sympathetic and ciliary ganglia was stimulated by GDNF at 50 ng/ml. The effects were not mimicked by the distant but related protein transforming growth factor beta 1 (TGF beta 1). The profile of neurons stimulated by GDNF is also distinct from the patterns of stimulation shown by nerve growth factor (NGF), stimulating strongly sympathetic but not ciliary ganglia, and ciliary neurotrophic factor (CNTF), stimulating mainly the ciliary ganglion. Moreover, using in situ hybridization histochemistry, GDNF was demonstrated to be present in the pineal gland in the newborn rat, a target organ for sympathetic innervation. The present results suggest that GDNF is likely to act upon receptors present in several autonomic and sensory neuronal populations. GDNF may serve to support fiber outgrowth and cell survival in peripheral ganglia, adding yet one more trophic factor to the list of specific proteins controlling development and maintenance of the peripheral nervous system.

Animals↗
PubMed1995

Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo.

Glial-cell-line-derived neurotrophic factor (GDNF), a recently cloned new member of the transforming growth factor-beta superfamily, promotes survival of cultured fetal mesencephalic dopamine neurons and is expressed in the developing striatum. There have, however, been no reports about effects of GDNF in situ. We have used the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces parkinsonian symptoms in man, to determine whether GDNF might exert protective or regenerative effects in vivo in the adult nigrostriatal dopamine system in C57/B1 mice. GDNF injected over the substantia nigra or in striatum before MPTP potently protects the dopamine system, as shown by numbers of mesencephalic dopamine nerve cell bodies, dopamine nerve terminal densities and dopamine levels. When GDNF is given after MPTP, dopamine levels and fibre densities are significantly restored. In both cases, motor behaviour is increased above normal levels. We conclude that intracerebral GDNF administration exerts both protective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment strategies for Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Glial cell line-derived neurotrophic factor reverses toxin-induced injury to midbrain dopaminergic neurons in vivo.

Fischer 344 rats were unilaterally injected into the medial forebrain bundle with 6-hydroxydopamine (6-OHDA). Apomorphine-induced rotational behavior was used to select animals whose rotation exceeded 300 turns/h, corresponding to greater than 95% dopamine (DA) depletion in the ipsilateral striatum. Four weeks later, glial cell line-derived neurotrophic factor (GDNF) or vehicle was injected intranigrally ipsilateral to the lesion (0.1-100 micrograms). The highest dose of GDNF tested produced a marked decrease in rotational behavior. This dose also produced levels of DA in the ipsilateral substantia nigra (SN) which were not statistically different from the contralateral side. Vehicle-treated animals showed a marked DA depletion in the ipsilateral SN. These results demonstrate neurochemical and behavioral improvements in unilaterally DA-lesioned rats following intranigral administration of GDNF, suggesting that GDNF may develop into a useful therapy for Parkinson's disease.

Animals↗
PubMed1994

Allogeneic grafts of fetal dopamine neurons: behavioral indices of immunological interactions.

Fetal central nervous system transplants to the adult brain have been utilized to understand brain connectivity and as replacement therapy in Parkinson's disease (PD). Here we use fetal brain allografting in the rat unilaterally depleted of dopamine, a unilateral model of PD, and apomorphine-induced rotations as an index of graft functional status while peripherally manipulating the host's alloimmune status. This system allows the investigator to examine, dynamically, host-allograft interactions in the brain under differing states of alloimmunoreactivity without the need to biopsy or sacrifice the animal. In addition to this novel application, we established that brain allografts are differentially susceptible to immunologic attack depending upon the graft's duration of residence in the host brain. Increasing residence time increases graft 'rejectability' to peripheral allosensitization. Passive immunization also sensitizes the host to subsequent graft rejection. Lastly, simple host alloimmunocompetence is necessary but not sufficient to cause fetal graft 'rejection', defined as a return of apomorphine-induced rotations.

Animals↗
PubMed1994

Chronic treatment with levodopa and/or selegiline does not affect behavioral recovery induced by fetal ventral mesencephalic grafts in unilaterally 6-hydroxydopamine-lesioned rats.

It has been suggested that levodopa (L-dopa), a dopamine precursor used to treat Parkinson's disease, may be toxic to grafted fetal neuroblasts; if so, the use of the monoamine oxidase B inhibitor selegiline might prevent such toxicity. We randomly assigned 30 unilaterally 6-hydroxydopamine-lesioned male Sprague-Dawley rats, whose lesions were verified with low-dose apomorphine-induced rotations, to one of five treatment groups: (i) L-dopa methyl ester (125 mg/kg/day) with benserazide (a peripheral decarboxylase inhibitor; 25 mg/kg/day), (ii) L-dopa methyl ester with benserazide and selegiline (L-deprenyl; 0.5 mg/kg/day), (iii) selegiline only, (iv) and (v) vehicle (ascorbate in normal saline) only. After 2 weeks of twice-daily ip injections, the rats received fetal ventral mesencephalic grafts into the lesioned striatum; one vehicle group received sham grafts. Drug therapy was continued for 2 1/2 months post grafting. At 1 month after grafting, and every 2 weeks thereafter, the rats were tested using low-dose apomorphine-induced rotation. A 70% decrease in rotations among all grafted groups, relative to the shams, was found. No statistical differences among groups receiving various drug therapies were seen in behavior or in counts or dimensions of tyrosine hydroxylase-positive cells. We therefore conclude that, in the unilaterally lesioned rat model of Parkinson's disease, there is no adverse effect of L-dopa nor any significant effect of selegiline, either alone or coadministered with L-dopa, on behavioral recovery induced by fetal ventral mesencephalic grafts.

Animals↗
PubMed1994

Conditioned apomorphine-induced turning in 6-OHDA-lesioned rats.

Apomorphine-induced turning has been used to evaluate the extent of unilateral nigrostriatal denervation after 6-hydroxydopamine (6-OHDA) lesions and subsequent functional striatal reinnervation by catecholaminergic grafts. It has been noted that the pregraft rotational pattern is usually double peaked and that fetal ventral mesencephalic grafts or dopaminergic drugs will alter the second peak but leave the first relatively unchanged. We hypothesized that the first peak may be the result of factors extrinsic to the nigrostriatal dopamine system, specifically a conditioned turning response, and would, therefore, be unperturbed by the above treatments which increase dopaminergic (DA) inputs. This was investigated by injecting 6-OHDA, unilaterally, into the nigrostriatal pathway of several groups of young Fisher 344 rats. One experimental group was repeatedly tested with 0.05 mg/kg apomorphine and the rotations quantified. A second group received similar injections of apomorphine but were prevented from rotating. Vehicle control animals were also studied for both of the above experimental groups. Subsequent to the above treatment, all animals were tested unrestrained repeatedly on apomorphine. Our results support the conditioned response hypothesis in that the first peak is not present with the initial unrestrained apomorphine behavioral trial but is present upon the second and subsequent unrestrained trials. Moreover, the restrained but apomorphine-injected rats, as well as the control animals, manifest no first peak upon their first freely moving apomorphine test; the second and subsequent unrestrained apomorphine trials, in these groups, do manifest a first peak.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Neuronal development in embryonic brain tissue derived from schizophrenic women and grafted to animal hosts.

The distribution of schizophrenia in families supports the hypothesis of heritable risk factors in schizophrenia, but there is as yet no identification of an inherited neurobiological defect. Human embryonic brain tissue fragments, derived from first trimester abortions, can be transplanted into rat hosts, where they continue neuronal development and are accessible for neurobiological investigation. Hippocampal transplants derived from three schizophrenic women and a larger series of normal women have been studied. If there are heritable neuronal defects associated with schizophrenia, a proportion of the transplants from schizophrenic women would be expected to carry these defects. The transplants from the first two schizophrenic women showed profound abnormalities in survival and growth, compared to the series of transplants from normal women. The transplants from the third schizophrenic woman showed normal growth and development, as well as typical histological and electrophysiological features. The data must be regarded as preliminary, because of the small number of subjects that have been studied. However, they are consistent with the transmission of a defect in neuronal development to some of the offspring of schizophrenic women, a possibility consistent with other studies of the pathogenesis of schizophrenia. The mechanism of the defect in development remains to be identified.

Adult↗
PubMed1994

Target and neurotransmitter specificity of fetal central nervous system transplants: importance for functional reinnervation.

The ability of grafted fetal ventral mesencephalic dopaminergic (DAergic) neuroblasts to reinnervate the unilaterally DA denervated rat striatum and improve motoric asymmetry has been well documented in several laboratories. The importance of host target specificity, and catecholamine (CA) neurotransmitter species, in the ability of grafts to ameliorate rotational responses to apomorphine and to affect electrophysiological characteristics of striatal neurons has not been systematically studied. We unilaterally lesioned Sprague-Dawley rats with 6-hydroxydopamine (6-OHDA) and verified the lesions using apomorphine (0.05 mg/kg, s.c.)-induced rotational behavior. Some of the animals subsequently received, intrastriatally, either DA neuroblasts from ventral mesencephalon that normally innervate the striatum, or from arcuate nucleus that do not. Additionally, two other groups were included that received either a CAergic graft from the noradrenergic nucleus locus coeruleus or a graft of cerebral cortex, which normally projects to the striatum but does not contain CAergic neurons. Only the fetal ventral mesencephalic grafts were able to reduce apomorphine-induced rotations and normalize striatal cell firing rates; striatal cell firing rates with ventral mesencephalic grafts were 1.43 Hz +/- 0.22, with arcuate nucleus grafts were 6.03 +/- 0.73, with locus coeruleus grafts were 4.71 +/- 0.74, and with cerebral cortex grafts were 4.36 +/- 0.45. Moreover, only the ventral mesencephalic grafts produced a dense tyrosine hydroxylase (TH)-immunoreactive nerve terminal network in the striatum; in contrast, the arcuate nucleus grafts did not reinnervate the striatum. In locus coeruleus grafted striata, few very long TH-positive axons were seen. We thus conclude that target specificity and neurotransmitter type are critically important in the ability of a graft to functionally reinnervate the 6-OHDA denervated striatum.

Animals↗
PubMed1994

Ethanol-induced depressions of cerebellar Purkinje neurons are potentiated by beta-adrenergic mechanisms in rat brain.

Electrophysiological studies indicate that EtOH decreases the firing rate of cerebellar Purkinje neurons in vivo and in vitro through a GABAA mechanism. These neurons receive a prominent noradrenergic input from the locus coeruleus. Stimulation of the locus coeruleus or local application of beta-adrenergic agonists potentiates Purkinje neuron responses to GABA and sensitizes GABA responses to the potentiative effects of EtOH. In the present study, we found that the modulatory influences of the beta-adrenergic agonist isoproterenol potentiated EtOH-induced depressions of Purkinje neuron firing. This isoproterenol interaction with EtOH was antagonized by the beta-adrenergic antagonist timolol. We found evidence that endogenous catecholamines can cause this effect as well. Timolol antagonized EtOH-induced depressions on 20% of the neurons studied. This was the same frequency as that previously found for EtOH-induced potentiations of GABA depressions in this brain area. These data suggest that the Purkinje neurons showing this interaction receive spontaneously active catecholamine inputs that sensitize the GABA effects to the potentiative effects of ethanol. Consistent with this hypothesis, we also found that timolol antagonized this GABA/EtOH interaction. Taken together, these results are consistent with the hypothesis that EtOH-induced depressions of Purkinje neurons involved endogenous GABA actions that may be regulated by beta-adrenergic mechanisms.

Animals↗
PubMed1993

Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats.

In the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease, controversy exists concerning the use of apomorphine- or D-amphetamine-induced rotations as reliable indicators of nigrostriatal dopamine depletion. Our objective was to evaluate which, if either, drug-induced behavior is more predictive of the extent of nigrostriatal dopamine depletion. Fischer 344 and Sprague-Dawley rats were unilaterally injected with 9 micrograms/4 microliters/4 min 6-hydroxydopamine into the medial forebrain bundle. The animals were behaviorally tested with apomorphine (0.05 mg/kg, s.c.) and D-amphetamine (5.0 mg/kg, s.c.). Following testing, the brains were removed and the right and left striata, substantia nigra and ventral tegmental area were dissected free and quickly frozen at -70 degrees C for analysis of catecholamine content by high performance liquid chromatography coupled with electrochemical detection. Our results indicate that an animal which has greater than a 90% depletion of dopamine in the striatum might not rotate substantially on apomorphine, without a concomitant depletion of > 50% of the DA content in the corresponding substantia nigra. No correlations were seen involving depletions of the ventral tegmental area and the extent of the lesions to the striatum. Submaximally lesioned (75-90% depleted) rats were found to rotate on D-amphetamine but not on apomorphine. In addition, control rats that did not receive lesions were often seen to rotate extensively on D-amphetamine. We therefore conclude that maximal lesions of the striatum and substantia nigra are required to generate rotations demonstrable with low dose apomorphine but not with D-amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1993

In vivo electrochemical measurements of exogenous dopamine clearance in normal and neonatal 6-hydroxydopamine-treated rat striatum.

The regulation of extracellular dopamine (DA) levels was studied in rat striatum after neonatal dopamine lesions and enhanced serotonin (5-HT) fiber ingrowth, induced with 6-hydroxydopamine (6-OHDA). We used rapid in vivo chronoamperometry combined with local DA applications. DA was pressure ejected in doses of 5 to 100 pmol at a distance of approximately 300 microns from the recording electrode, using single- or multibarrel glass micropipettes. Almost twice as much DA had to be applied in control rat dorsal and ventral striatum to obtain signals comparable to those recorded in the neonatal 6-OHDA-treated animals. In addition, in the dorsal striatum, the later portions of the DA clearance signals were significantly prolonged in the 6-OHDA group. Some clearance decay times in ventral striatum were also significantly prolonged in the neonatal 6-OHDA-treated rats. Concomitant application of the DA uptake inhibitor, nomifensine, in conjunction with the DA ejections, produced signal characteristics in the control striatum that were similar to those seen in the neonatal 6-OHDA-treated striatum. Taken together, these data support the hypothesis that a major component of the clearance of extracellular DA is dependent on intact terminals with high-affinity DA uptake, and that loss of DA afferents from neonatal 6-OHDA treatment results in a slowed clearance time of extracellular DA which is not apparently compensated by the enhanced 5-HT fiber ingrowth.

Animals↗
PubMed1993

In vivo electrochemical measurements and electrophysiological studies of rat striatum following neonatal 6-hydroxydopamine treatment.

The effects of neonatal treatment (one day after birth) with the neurotoxin, 6-hydroxydopamine (75 micrograms/10 microliters intracisternal), were studied in the striatum of normal adult and treated Sprague-Dawley rats. Measurements of monoamine levels in the dorsal striatum and nucleus accumbens, by high-performance liquid chromatography coupled with electrochemical detection, showed that neonatal 6-hydroxydopamine treatment produced a permanent and massive destruction of striatal dopamine. The effects were more pronounced in the dorsal striatum than in the nucleus accumbens. In addition, serotonin levels were elevated in the rat striatum as a consequence of the neonatal treatment. Rapid chronoamperometric recordings of K(+)-evoked monoamine overflow using Nafion-coated recording electrodes were investigated in both the dorsal and ventral striatum of control and neonatally lesioned rats. The potassium-evoked responses recorded from the dorsal striatum of the 6-hydroxydopamine-treated rats were significantly reduced in amplitude as compared to controls. In addition, the reduction/oxidation current ratios of the responses were more serotonin-like, in contrast to the dopamine-like current ratios measured in the striatum of untreated animals. In ventral striatum, the amplitudes of the K(+)-evoked responses were not significantly reduced versus control. However, the K(+)-evoked signals were more serotonin-like in their electrochemical characteristics as compared to controls. In addition to the release studies, extracellular single-unit electrophysiological recordings were performed in normal and neonatally 6-hydroxydopamine-treated rats. The spontaneous discharge rate of striatal neurons in the neonatally 6-hydroxydopamine-treated rats was similar to that of control rats. This is in contrast to dopamine lesions in adult animals, where a marked elevation of the discharge rate is observed. Local applications of dopamine and serotonin into the striatum of neonatally 6-hydroxydopamine-treated rats elicited excitations of striatal cells rather than the normal inhibitory effects seen in control animals. Taken together, these data suggest that loss of striatal dopamine terminals at birth leads to both pre- and postsynaptic alterations in monoamine pathways.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

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.

Adult↗