Animal models of Lesch-Nyhan syndrome.

In humans, deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) is associated with a disorder known as Lesch-Nyhan syndrome which includes severe neurobehavioral abnormalities. Several animal models which have been developed to examine the neurobiologic substrates of this disorder have suggested a role for abnormal function in purine/dopamine neurotransmission, but the relationship between HPRT-deficiency and these abnormalities remains unknown. Recently, HPRT-deficient mice have been produced which appear to have similar, though more subtle changes in brain dopamine function.

Differential expression of protein kinase C isozymes in rat cerebellum.

Protein kinase C (PKC) is a family of enzymes found throughout the body, with the greatest diversity and concentration in brain tissue. To understand further the differential role of PKC isozymes in brain, we have raised antibodies against four PKC isoforms--alpha, beta I, beta II and gamma--using specific amino acid sequences predicted from cDNA sequences. On Western blot of rat cerebellar homogenate, these antibodies stained a band of Mr 80,000, a known molecular mass for PKC, except for anti-PKC(beta II), which stained an additional minor Mr 90,000 band.

Nucleus basalis lesions fail to induce senile plaques in the rat.

Fourteen months after receiving bilateral ibotenic acid lesions of the nucleus basalis magnocellaris (NBM), male rats demonstrated impairment in spatial learning in a water maze task, increased incidence of high voltage spindles, and significant depletion of cortical choline acetyltransferase (ChAT) activity. Histological evaluation revealed decreased acetylcholinesterase (AChE) staining but no plaque-like structures in the cortex.

Altered levels of amyloid protein precursor transcripts in the basal forebrain of behaviorally impaired aged rats.

The beta/A4 protein is a constituent of plaque and vascular amyloid deposits in Alzheimer disease. Previous studies have shown increased levels of amyloid protein precursor (APP) mRNA in basal forebrain neurons in the disease. Morphological and neurochemical changes occur within the forebrain in Alzheimer disease and are also correlated with behavioral impairments in aged rats.

Basal forebrain cell loss following fimbria/fornix transection.

Following fimbria/fornix transection, cells in the medial septum appear to undergo retrograde degeneration as shown by Nissl and acetylcholine esterase (AChE) staining. Recent studies using immunocytochemical techniques have also demonstrated loss of choline acetyltransferase (ChAT) and nerve growth factor receptor (NGFr) labeling of neurons in this region. Whether the apparent loss of ChAT- and NGFr-positive neurons is the result of the actual death of these neurons, or is instead a loss of ChAT enzyme or NGFr expression below levels detectable by immunocytochemical methods, remains an unresolved issue.

NGF-dependent sprouting and regeneration in the hippocampus.

While a variety of sprouting and regenerative responses have been investigated in the hippocampus, the cellular and molecular events responsible for these plastic responses have not been determined. One transmitter system, the cholinergic system, shows several distinct responses to damage in the septohippocampal circuit. Present evidence strongly supports a role for nerve growth factor (NGF) in these responses.

Spatial organization of physiological activity in the hippocampal region: relevance to memory formation.

Based on a review of anatomical and physiological findings, we suggest that the hippocampus may be viewed as a positive feedback device (autoassociator), which is capable of modifying the activity of the neocortical neurons. We examine the three-dimensional organization of evoked and spontaneous physiological patterns of the hippocampus and suggest rules how these patterns emerge during different behaviors from a hard-wired structural network. The high spatial coherence of theta activity is due to an external pacemaker, while the high synchrony of population bursts underlying hippocampal sharp waves is explained by the similar probability of recruitment of neurons by the burst-initiator cells along the whole extent of the hippocampus.

Potential use of neurotrophic agents in the treatment of neurodegenerative disorders.

The use of neurotrophic agents as therapy for neurodegenerative disorders was originally proposed several years ago (1). Since then, several lines of evidence have converged to support the consideration of neurotrophic factor therapy for clinical disorders. In particular, the cholinergic neuronal atrophy that occurs in Alzheimer's disease has been identified as a strong potential candidate for the first clinical trials of nerve growth factor (NGF) in a human neurodegenerative disorder.

Petit mal epilepsy and parkinsonian tremor: hypothesis of a common pacemaker.

Rhythmic oscillation in neuronal systems may serve physiological purposes or may interfere with normal functions of the brain. In disorders of petit mal epilepsy and parkinsonian tremor, centrally and peripherally observable rhythmic patterns are due to network oscillations of thalamocortical cells. This article reviews the afferent mechanisms that might be critically involved in controlling the ionic conductances of thalamic neurons in the behaving organism.

Autocrine differentiation of PC12 cells mediated by retroviral vectors.

Rat pheochromocytoma PC12 cells have been modified genetically by the use of replication-defective retroviral vectors containing either the bacterial gene for beta-galactosidase (lac Z) or cDNAs for mouse beta-nerve growth factor (NGF) and the bacterial gene for neomycin resistance. Using the lac Z vector, clonal lines of PC12 cells were obtained in which almost 100% of cells stably expressed this histochemical marker. Infection of PC12 cells or the derived subclone PC12-BAG, which expresses beta-galactosidase, with the NGF vectors resulted in autocrine differentiation as assessed by extensive neurite formation, which occurred within hours after infection and was maintained for weeks in culture.

Gene therapy in the CNS: intracerebral grafting of genetically modified cells.

Grafting cells to the CNS has been suggested and applied as a potential approach to CNS therapy through the selective replacement of cells lost as a result of disease or damage. Independently, studies aimed at direct genetic therapy in model systems have recently begun to suggest conceptually new approaches to the treatment of several kinds of human genetic disease, especially those caused by single gene enzyme deficiencies. We suggest that a combination of these two approaches, namely the graftment into the CNS of genetically modified cells, may provide a new approach toward the restoration of some functions in the damaged or diseased CNS.

Dopaminergic cells align along radial glia in the developing mesencephalon of the rat.

Studies were performed to examine the relation of dopaminergic cells and radial glia in the developing mesencephalon of the rat at ages E12-E20. Dopaminergic cells were immunolabelled with an antiserum which recognizes tyrosine hydroxylase, and radial glia were immunolabelled with a monoclonal antibody which recognizes vimentin. The vimentin-immunoreactive fibres of radial glia were noted at E12.

Nerve growth factor infusions combined with fetal hippocampal grafts enhance reconstruction of the lesioned septohippocampal projection.

A combination of intracerebral grafting and intraventricular infusion of nerve growth factor was used to attempt to reconstruct the cholinergic component of the septohippocampal pathway following fimbria-fornix lesions in the rat. Four groups were tested: lesion only, lesion plus fetal hippocampal graft, lesion plus nerve growth factor, and lesion plus graft plus nerve growth factor. Choline acetyltransferase immunoreactivity, acetylcholinesterase fiber staining and behavior-dependent theta activity on electroencephalogram were used to assess the extent of pathway reconstruction.

Normalization of subtype-specific muscarinic receptor binding in the denervated hippocampus by septodiagonal band grafts.

Unilateral fimbria-fornix lesions were made by aspiration in female Sprague-Dawley rats. In a group of these rats, fetal septal tissue was transplanted into the lesion cavity. Lesion of the fimbria-fornix resulted in a reduction of cholinergic input to the hippocampal formation as indicated by the loss of acetylcholinesterase (AChE)-positive staining in all ipsilateral hippocampal laminae and a loss of [3H]hemicholinium-3 binding to cholinergic terminals in the strata oriens (82% reduction) and radiatum (77% reduction) of areas CA2 and CA3 and in the molecular layer of the dentate gyrus (83% reduction).

Delivery of neuroactive compounds to the brain: potential utility of genetically modified cells.

Several methods for chronic delivery of compounds to the central nervous system (CNS) now exist. Peripheral drug administration is generally safest, but not always effective. If direct CNS delivery of a substance is required, then CNS implantation of drug-delivery systems or grafting of various cell types to the brain can be performed, although none of these interventions are yet of consistent, proven benefit in Alzheimer's disease and other neurodegenerative disorders.

Role of neurotrophic factors in Alzheimer's disease.

Neurotrophic factors (NTFs) could potentially play a role in Alzheimer's disease (AD) in many ways. Neuronal degeneration may result from disruption in NTF production, delivery, or interaction with the neuronal target. Even if alterations in NTF function are not responsible for neuronal degeneration, NTFs may still be therapeutically useful in ameliorating some morphological or cognitive deficits observed in AD.

NGF induction of NGF receptor gene expression and cholinergic neuronal hypertrophy within the basal forebrain of the adult rat.

Chronic infusion of nerve growth factor (NGF) into the forebrain of the adult rat produced increases in NGF receptor (NGF-R) mRNA hybridization, NGF-R immunoreactivity, choline acetyltransferase (ChAT) mRNA hybridization, and neuronal hypertrophy, when compared with vehicle infusion or noninfused rat brain. In situ hybridization showed NGF induction of NGF-R gene expression, documented by increases in the number of NGF-R mRNA-positive cells within the medial septum, diagonal band, and nucleus basalis magnocellularis. NGF also produced hypertrophy of ChAT mRNA-positive neurons.

The grafted hippocampus: an epileptic focus.

Field potentials and unitary activity were investigated in the grafted and the host hippocampi in freely moving rats and in vitro. The subcortical afferents and efferents of the hippocampus (fimbria-fornix, FF) were removed by aspiration. Solid pieces of hippocampal grafts derived from 15- to 16-day-old fetuses were placed in the lesion cavity in rats with unilateral FF lesions, and cell suspensions prepared from fetal hippocampi were grafted directly into the host hippocampi in animals with bilateral FF lesions.

Age-related impairments in spatial memory are independent of those in sensorimotor skills.

Seventy-five aged rats were tested for a variety of motor and cognitive tests which generated 20 separate measures of performance. Considerable variability was observed on many measures in the aged population. Multivariate analyses were performed on the data to determine 1) the extent of intercorrelations between the measures for the aged rats, and 2) whether clusters of related and/or unrelated behavioral measures could be determined.

Nerve growth factor receptor and choline acetyltransferase colocalization in neurons within the rat forebrain: response to fimbria-fornix transection.

Although it is well known that magnocellular cholinergic basal forebrain neurons are trophically responsive to nerve growth factor (NGF) and contain NGF receptors (NGFr), the exact distribution of forebrain NGFr-immunoreactive neurons and the degree to which cholinergic neurons are colocalized with them have remained in question. In this study we employed a very sensitive double-labelling method and examined in the same tissue section the distribution and cellular features of NGFr-positive and choline acetyltransferase (ChAT)-immunolabelled neurons within the rat basal forebrain. Throughout this region the majority of magnocellular basal forebrain neurons were immunoreactive for both NGFr and ChAT.