Lars Olson

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.

Thy-1-like immunoreactivity in human brain during development

Thy-1-like immunoreactivity was found in several areas of the immature and adult human brain, using indirect immunofluorescence techniques. In the fetal brain (31 gestational weeks) most immunoreactivity was located in the white matter with an overall granular diffuse distribution and stray fluorescent fibrous structures radiating into grey matter. At 2 months postnatally, the large axon bundles of the internal capsule traversing the caudate nucleus were strongly positive, whereas surrounding neuropil seemed to be negative. In the adult caudate nucleus no such fluorescent fibre bundles could be observed. At 8 months of age, both cerebellum and frontal cerebral cortex contained large numbers of fibrous structures in the grey matter in addition to white matter fluorescence. The molecular layer of both areas was negative. The 8-month-old cerebellum had a Thy-1 distribution similar to the adult, while in the frontal cortex cerebri the density of fluorescent structures increased gradually until adulthood. However, in the 5-year-old frontal cortex the immature granular appearance of 2-month-old cortex could still be seen, but with a greater number of radiating fluorescent bundles. In the adult brain, cerebellum contained a dense pattern of thick, fibrous fluorescent structures in white matter and the internal granular layer and in the frontal cortex thick bundles radiated into grey matter to form a plexus of coarse individual fibres in layers II and III. The hippocampal formation of the 31-week-old fetus contained a network of thin varicose fibres, ascending from the white matter. Stratum radiatum at this stage contained numerous small spots of Thy-1-like immunoreactivity, but no visible fluorescent fibres.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of β-Nerve Growth Factor and its Receptor in the Mammalian Central Nervous System

β-nerve growth factor (NGF) is a target derived protein that in the peripheral nervous system (PNS) is required for the development and maintenance of sympathetic and sensory neurons (LeviMontalcini and Angeletti, 1968; Thoenen and Barde, 1980). NGF mediates its neurotrophic effects by interacting with specific NGF receptors (NGF-R), which in the PNS have been found on the cell surface of sympathetic and sensory neurons (Banerjee et al., 1973: Herrup and Shooter, 1973). The NGF bound to its receptor is internalized by receptor-mediated endocytosis and is transported from nerve terminals to the neuronal cell body (Hendry et al., 1974; Stockel et al., 1974; 1976), where NGF induces several metabolic alterations in the responsive neuron (Schwab et al., 1981; Layer and Shooter, 1983).

Activity and Immunological Properties of Recombinant Nerve Growth Factor (β-NGF)

Nerve growth factor (βNGF) is a basic 118-amino acid protein acting as a trophic factor for many sensory and sympathetic neurons in the peripheral nervous system (Levi-Montalcini and Angeletti, 1968; Thoenen and Barde, 1980; Levi-Montalcini, 1987). The pioneering studies on NGF by Rita Levi-Montalcini and Victor Hamburger in the early 1950’s showed a marked stimulation by NGF on nerve fibre formation, neuron survival and neuron maturation in the sympathetic and some sensory ganglia of the developing peripheral nervous system (Levi-Montalcini and Hamburger, 1953). Nerve growth factor has recently also been found in the brain (Korsching et al., 1985; Whittemore et al., 1986; Shelton & Reichardt, 1986; Goedert et al., 1986) where it serves a trophic function for cholinergic neurons situated in the basal forebrain (Korsching et al.,1985; Large et al., 1986; Richardson et al., 1986; Larkfors et al., 1987b; review by Ebendal, 1989a).

Strategies to Increase NGF Levels and Effects thereof on Lesioned and Grafted Brain Tissue

Mounting evidence indicates important roles for nerve growth factor (NGF) in the developing and mature central nervous system where cholinergic systems appear to be a prime target for NGF (see Dreyfus, 1989a; Ebendal, 1989; Persson et al., this volume; Thoenen et al., 1987; Whittemore and Seiger, 1987). While the sensitivity to NGF might differ during development and between different transferase (ChAT) and NGF receptor (NGF-R) immunoreactivity in both rodents and primates including man (Batchelor et al., 1989; Dawbarn, 1988; Hefti and Mash, 1989; Kordower et al., 1988, 1989; Mesulam et al., 1989; Mufson et al., 1989; Woolf et al., 1989). However, both during development and in the adult nervous system, NGF-R has a more widespread distribution than the cholinergic systems, being prominent, e.g. also in cerebellum and several other areas (Buck et al., 1988; Ernfors et al., 1988), suggesting that also non-cholinergic systems might be NGF-sensitive. Indeed, there are reports of colocalization of NGF-R and GABA uptake (Arimatsu and Miyamoto, 1989; Dreyfus et al., 1989b). Of particular interest is the fact that the major cholinergic projection systems from septum to hippocampus and from basal forebrain to cortex cerebri depend on NGF produced by the target areas. Thus, when the septo-hippocampal pathway is lesioned, the axotomized cholinergic neurons can be rescued by injection of exogenous NGF (Kromer, 1987; Williams et al., 1986). There is a loss of cholinergic neurons in the forebrain during normal aging (Bartus et al., 1982) and in senile dementia of Alzheimer’s type, this loss is markedly accelerated (Whitehouse et al., 1982). However, remaining cholinergic neurons in Alzheimer’s disease appear to have sufficient levels of NGF-R mRNA and NGF-R (Goedert et al., 1989; Kordower et al., 1989), suggesting that these neurons continue to be NGF-sensitive and therefore that NGF might be beneficial in the senile dementias.