Stiff-man syndrome is a rare disorder of the central nervous system consisting of progressive, fluctuating muscle rigidity with painful spasms. It is occasionally associated with endocrine disorders, including insulin-dependent diabetes, and with epilepsy. We investigated the possible existence of autoimmunity against the nervous system in a patient with stiff-man syndrome associated with epilepsy and Type I diabetes mellitus. Levels of IgG, which had an oligoclonal pattern, were elevated in the cerebrospinal fluid. The serum and the cerebrospinal fluid produced an identical, intense staining of all gray-matter regions when used to stain brain sections according to an indirect light-microscopical immunocytochemical procedure. The staining patterns were identical to those produced by antibodies to glutamic acid decarboxylase (the enzyme responsible for the synthesis of gamma-aminobutyric acid). A band comigrating with glutamic acid decarboxylase in sodium dodecyl sulfate-polyacrylamide gels appeared to be the only nervous-tissue antigen recognized by cerebrospinal fluid antibodies, and the predominant antigen recognized by serum antibodies. These findings support the idea that an impairment of neuronal pathways that operate through gamma-aminobutyric acid is involved in the pathogenesis of stiff-man syndrome, and they raise the possibility of an autoimmune pathogenesis.

Neuronal proliferation, migration, and differentiation are regulated by the sequential expression of particular genes at specific stages of development. Such processes rely on differential gene expression modulated through second-messenger systems. Early postnatal mouse cerebellar granule cells migrate into the internal granular layer and acquire differentiated properties. The neurotransmitter glutamate has been shown to play an important role in this developmental process. We show here by immunohistochemistry that the RelA subunit of the transcription factor NF-acB is present in several areas of the mouse brain. Moreover, immunofluorescence microscopy and electrophoretic mobility-shift assay demonstrate that in cerebellar granule cell cultures derived from 3-to 7-day-old mice, glutamate specifically activates the transcription factor NF-KB, as shown by binding of nuclear extract proteins to a synthetic oligonucleotide reproducing the KB site of human immunodeficiency virus. The use of different antagonists of the glutamate receptors indicates that the effect of glutamate occurs mainly via N-methyl-D-aspartate (NMDA)-receptor activation, possibly as a result of an increase in intracellular Ca2+. The

The shape of a neurone--the projection and branching pattern of axons and dendrites--appears to be determined by a combination of intrinisic and environmental influences. We have previously shown that striatal target neurones influence the biochemical maturation of ascending mesencephalic dopamine (DA) cells in culture, as well as the elongation rate of DA neurites. Using a similar approach in which the morphology of individual DA cells can be studied after 3H-DA uptake and autoradiography, we now report on in vitro neurone-glia interactions and show that glial cells exert a morphogenetic effect on DA neurones. Dopaminergic neurones from the mesencephalon were plated on glial monolayers prepared either from the striatal or the mesencephalic region of the embryonic brain. On mesencephalic glial cells the majority of DA neurones develop a great number of highly branched and varicose neurites, whereas on striatal glia they only exhibit one long, thin and rather linear neurite. These results demonstrate that glial cells from two different brain regions have distinct properties which could be used to define neuronal polarity observed in vivo.

Neurogenesis proceeds throughout adulthood in the brain of most mammalian species, but the molecular mechanisms underlying the regulation of stem/progenitor cell proliferation, survival, maturation, and differentiation have not been completely unraveled. We have studied hippocampal neurogenesis in NF-B p50-deficient mice. Here we demonstrate that in absence of p50, the net rate of neural precursor proliferation does not change, but some of the steps leading to the final neuron differentiation status are hampered, resulting in ϳ50% reduction in the number of newly born neurons in the adult mutant hippocampus. Additionally, in p50 Ϫ/Ϫ mice, we observed a selective defect in short-term spatial memory performance without impairment of hippocampal-dependent spatial long-term memory and learning. Our results highlight the role of NF-B p50 in hippocampal neurogenesis and in short-term spatial memory.

Microglial cells are non‐professional antigen‐presenting cells (APC) the function of which is still controversial. Here, we studied the function of microglia derived from H‐2u mice. We show that these microglia express a low level of B7.2 and CD40 and, interestingly, lack surface expression of B7.1. Resting and IFN‐γ‐activated microglia were unable to activate naive and primed myelin basic protein (MBP)‐specific CD4+ T cells in the presence of MBP and encephalomyelitic MBP Ac1‐11 peptide. Furthermore, in the presence of Ac1‐11 peptide, CD4+ TCR‐transgenic T cells became anergized. Microglia became professional APC only after a multistep activation process involving both stimulation through cytokines [granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and IFN‐γ] and cognate signaling (B7‐CD28 and CD40‐CD40 ligand interactions). As such they were able to present MBP to both unprimed and primed T cells. Co‐culture of microglia with GM‐CSF up‐regulated co‐stimulatory molecules, in particular B7.1. Additional activation with IFN‐γ induced MHC class II and CD40 up‐regulation. CD40‐CD40 ligand interaction significantly enhanced microglial ability to prime TCR‐transgenic T cells and was essential for presentation of MBP to in vivo primed non‐transgenic T cells. We propose that microglia may serve different functions under different inflammatory conditions, depending on the cytokine milieu and the type of cognate interaction they are involved in.

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In the olfactory bulb, tyrosine hydroxylase (TH), the rate-limiting enzyme in the biosynthesis of catecholamines, is expressed after birth when the axons of olfactory epithelial neurons have made synapses in the bulb. It has been suggested that expression of TH is regulated trans-synaptically because on deafferentation of the bulb there is a marked decrease in the contents of TH, dopamine and 3,4-dihydroxyphenylacetic acid, which, however, return to normal levels after regeneration of the primary afferents. To date the molecular signalling involved in this trans-synaptic induction has not yet been characterized; I have therefore studied the expression of dopaminergic properties (presence of TH and dopamine uptake) in dissociated cell cultures from embryonic mouse olfactory bulb. I report that the number of dopaminergic cells increases fivefold when olfactory bulb neurons are co-cultured with olfactory epithelial neurons and that soluble factors, rather than cell interactions, mediate this effect. The dopaminergic-inducing factor is the calcitonin gene-related peptide (CGRP) which is present in chemosensory neurons of the olfactory epithelium and when added at nanomolar concentrations to olfactory bulb cultures mimics the effect of olfactory epithelial neurons. Significantly the induction of dopaminergic phenotypes brought about by olfactory epithelial neurons is abolished by an antiserum to CGRP. These observations show that CGRP is involved in the differentiation of dopaminergic olfactory bulb neurons.