No abstract

CILIARY neurotrophic factor (CNTF) supports the survival of embryonic motor neurons in vitrol,2 and in vivo 3 and prevents lesion-mediated degeneration of rat motor neuron~ during early post-natal stages 4• Here we report that CNTF greatly reduces all the functional and morphological changes in pmnlpmn mice 5 , an autosomal recessive mutant leading to progressive caudo-cranial motor neuron degeneration. The first manifestations of progressive motor neuronopathy in homozygous pmnl pmn mice become apparent in the hind limbs at the end of the third post-natal week and all the mice die up to 6 or 7 weeks after birth from respirato~ ~aralysis. Treatment .with CNTF p-rolongs-survival-and greatly Imp~oves ~otor functIon of these mice. Moreover, morphological mamfestatJons, such as loss of motor axons in the phrenic nerve and degeneration of facial motor neurons, were greatly reduced by CNTF, although the treatment did not start until the first symptoms of the disease had already become apparent and substan-' tial degenerative changes were already present. The protective and r~storative effects of CNTF in this mouse mutant give new perspectIves for the treatment of human degenerative motor neuron diseases with CNTF.We hav~ e~aluate~ the effects of CNTF in the pmn/ pmn mouse, whIch IS an ammal model for human spinal motor neuron disease 5 . In contrast to two other mouse mutants wobbler 6 -8 and mnd 9,1O, the manifestations of motor neuron d~generation in pmn/ pmn mice appear earlier and progress more rapidly. In 4-wee~-0Id pmn/ pmn mice, the number ofaxons of the phrenic nerve IS already highly reduced, indicating that at this time the Number of phrenic nerve axonsThe brain stem of mice perfused with 4% formaldehyde was embedded in paraffin, serial sections 7 -fLm thick were stained with cresyl violet, and the nucleoli of facial motor neurons were counted in every fifth section on both sides as previously described" Counts were not corrected for spl it nucleoli 4 ,15, The mean of the counts on both sides was used for each animal. Phrenic nerves were prepared after perfusion of the animals with 4% formalin, Nerves were postfixed in 4% formalin, dehydrated, then 5-fLm transverse sections made and stained according to ref, 16, Myelinated axons were counted from photographs taken from nerve sections under the light microscope, Data shown are means ± s,e.m, for each group, ND, not determined, * Statistical significance was tested by Student's t-test, P< 0,0005, 502 disease has already reached an advanced stage. The motor neurons of pmn/ pmn mice first undergo a reduction in cell size, then chromatolysis and finally cell death, similar to the pathological changes seen in many cases of human motor neuron diseases ll. The gene defect responsible for the motor neu'ron changes in pmn/ pmn mice is still unknown. But an insufficient or defective expression of CNTF does not seem to be responsible for the degenerative changes. Northern blots of sciatic nerve reveal CNTF transcripts with similar size and intensity to those of the h...

Microglia are the source of the resident macrophages of the brain and thus belong to one of the most reactive cell types in cerebral tissue. They are attributed to have an important role in a number of pathological conditions, such as multiple sclerosis, viral infections like AIDS, and in lethal or sublethal injuries of neurons where the blood-brain barrier is left intact (Streit et al., 1988; McGeer et al., 1988; Gendelman et al., 1989). Microglia share a number of macrophage characteristics but so far lack a distinguishing positive marker. In this study it is shown that microglia are distinguished from other macrophages by a unique pattern of ion channels. We compared membrane currents of microglial cells with those from peritoneal macrophages cultured under identical conditions. Although in macrophages a delayed outward K+ current was previously described (Randriamampita and Trautmann, 1987), microglial cells lacked any specific outward current. Instead, these cells were characterized by large inwardly rectifying currents, activated by hyperpolarizing voltage steps. The reversal potential in different K+ gradients and the sensitivity of the current to to Ba2+, TEA, and 4-AP indicates that this current is K+ selective. In single-channel recordings, a 30 pS K+ selective channel similar to the classical inward rectifier K+ channel was observed. Thus, the expression of membrane channels served not only to distinguish microglia from other cells inside and outside the brain, e.g., blood macrophages, but also suggests a unique functional state of this cell population.

Axotomy of the rat facial nerve leads to mitotic divisions of microglial cells without developing into phagocytes. In order to study the functional characteristics of those activated, i.e., proliferating but nonphagocytic, microglia we investigated the expression of monocyte/macrophage antigens by these cells. Our results show that activated microglia lack monocyte/macrophage antigens recognized by the monoclonal antibodies Ox-41, ED1, ED2, and Ki-M2R but express high levels of CR3 complement receptors in situ.

Activation and proliferation of microglia are common cellular hallmarks in many different pathological processes of the central nervous system. Although a number of colony-stimulating factors enhance microglial proliferation in vitro, little is known about the endogenous mitogens. In the present study we show a strong and selective inhibition of microglial proliferation in the facial nucleus of osteopetrotic (op/op) mice, with a genetic deficiency in biologically active macrophage colony-stimulating factor (MCSF). Posttraumatic activation of adjacent axotomized neurons and reactive astrocytes was not affected, emphasizing the specificity of MCSF as a microglial growth factor.