Cardiotrophin-like cytokine/cytokine-like factor 1 is an essential trophic factor for lumbar and facial motoneurons in vivo

The ciliary neurotrophic factor alpha-receptor(CNTFRalpha) is required for motoneuron survival during development, but the relevant ligand(s) has not been determined. One candidate is the heterodimer formed by cardiotrophin-like cytokine (CLC) and cytokine-like factor 1 (CLF). CLC/CLF binds to CNTFRalpha and enhances the survival of developing motoneurons in vitro; whether this novel trophic factor plays a role in neural development in vivo has not been tested. We examined motor and sensory neurons in embryonic chicks treated with CLC and in mice with a targeted deletion of the clf gene. Treatment with CLC increased the number of lumbar spinal cord motoneurons that survived the cell death period in chicks. However, this effect was regionally specific, because brachial and thoracic motoneurons were unaffected. Similarly, newborn clf -/- mice exhibited a significant reduction in lumbar motoneurons, with no change in the brachial or thoracic cord. Clf deletion also affected brainstem motor nuclei in a regionally specific manner; the number of motoneurons in the facial but not hypoglossal nucleus was significantly reduced. Sensory neurons of the dorsal root ganglia were not affected by either CLC treatment or clf gene deletion. Finally, mRNA for both clc and clf was found in skeletal muscle fibers of embryonic mice during the motoneuron cell death period. These findings support the view that CLC/CLF is a target-derived factor required for the survival of specific pools of motoneurons. The in vivo actions of CLC and CLF can account for many of the effects of CNTFRalpha on developing motoneurons.

Molecular structure and function of the glycine receptor chloride channel

The glycine receptor chloride channel (GlyR) is a member of the nicotinic acetylcholine receptor family of ligand-gated ion channels. Functional receptors of this family comprise five subunits and are important targets for neuroactive drugs. The GlyR is best known for mediating inhibitory neurotransmission in the spinal cord and brain stem, although recent evidence suggests it may also have other physiological roles, including excitatory neurotransmission in embryonic neurons. To date, four alpha-subunits (alpha1 to alpha4) and one beta-subunit have been identified. The differential expression of subunits underlies a diversity in GlyR pharmacology. A developmental switch from alpha2 to alpha1beta is completed by around postnatal day 20 in the rat. The beta-subunit is responsible for anchoring GlyRs to the subsynaptic cytoskeleton via the cytoplasmic protein gephyrin. The last few years have seen a surge in interest in these receptors. Consequently, a wealth of information has recently emerged concerning Glyl? molecular structure and function. Most of the information has been obtained from homomeric alpha1 GlyRs, with the roles of the other subunits receiving relatively little attention. Heritable mutations to human GlyR genes give rise to a rare neurological disorder, hyperekplexia (or startle disease). Similar syndromes also occur in other species. A rapidly growing list of compounds has been shown to exert potent modulatory effects on this receptor. Since GlyRs are involved in motor reflex circuits of the spinal cord and provide inhibitory synapses onto pain sensory neurons, these agents may provide lead compounds for the development of muscle relaxant and peripheral analgesic drugs.

Visual feedback alters the variations in corticospinal excitability that arise from rhythmic movements of the opposite limb

Augmented visual feedback can have a profound bearing on the stability of bimanual coordination. Indeed, this has been used to render tractable the study of patterns of coordination that cannot otherwise be produced in a stable fashion. In previous investigations (Carson et al. 1999), we have shown that rhythmic movements, brought about by the contraction of muscles on one side of the body, lead to phase-locked changes in the excitability of homologous motor pathways of the opposite limb. The present study was conducted to assess whether these changes are influenced by the presence of visual feedback of the moving limb. Eight participants performed rhythmic flexion-extension movements of the left wrist to the beat of a metronome (1.5 Hz). In 50% of trials, visual feedback of wrist displacement was provided in relation to a target amplitude, defined by the mean movement amplitude generated during the immediately preceding no feedback trial. Motor potentials (MEPs) were evoked in the quiescent muscles of the right limb by magnetic stimulation of the left motor cortex. Consistent with our previous observations, MEP amplitudes were modulated during the movement cycle of the opposite limb. The extent of this modulation was, however, smaller in the presence of visual feedback of the moving limb (FCR omega(2) =0.41; ECR omega(2)=0.29) than in trials in which there was no visual feedback (FCR omega(2)=0.51; ECR omega(2)=0.48). In addition, the relationship between the level of FCR activation and the excitability of the homologous corticospinal pathway of the opposite limb was sensitive to the vision condition; the degree of correlation between the two variables was larger when there was no visual feedback of the moving limb. The results of the present study support the view that increases in the stability of bimanual coordination brought about by augmented feedback may be mediated by changes in the crossed modulation of excitability in homologous motor pathways.

Glycinergic and GABAergic synaptic activity differentially regulate motoneuron survival and skeletal muscle innervation

GABAergic and glycinergic synaptic transmission is proposed to promote the maturation and refinement of the developing CNS. Here we provide morphological and functional evidence that glycinergic and GABAergic synapses control motoneuron development in a region-specific manner during programmed cell death. In gephyrin-deficient mice that lack all postsynaptic glycine receptor and some GABA(A) receptor clusters, there was increased spontaneous respiratory motor activity, reduced respiratory motoneuron survival, and decreased innervation of the diaphragm. In contrast, limb-innervating motoneurons showed decreased spontaneous activity, increased survival, and increased innervation of their target muscles. Both GABA and glycine increased limb-innervating motoneuron activity and decreased respiratory motoneuron activity in wild-type mice, but only glycine responses were abolished in gephyrin-deficient mice. Our results provide genetic evidence that the development of glycinergic and GABAergic synaptic inputs onto motoneurons plays an important role in the survival, axonal branching, and spontaneous activity of motoneurons in developing mammalian embryos.

The role of group I metabotropic glutamate receptor's in neuronal excitotoxicity in Alzheimer's disease

Neurodegenerative diseases such as Huntington's disease, ischemia, and Alzheimer's disease (AD) are major causes of death. Recently, metabotropic glutamate receptors (mGluRs), a group of seven-transmembrane-domain proteins that couple to G-proteins, have become of interest for studies of pathogenesis. Group I mGluRs control the levels of second messengers such as inositol 1,4,5-triphosphate (IP3) Cal(2+) ions and cAMP. They elicit the release of arachidonic acid via intracellular Ca2+ mobilization from intracellular stores such as mitochondria and endoplasmic reticulum. This facilitates the release of glutamate and could trigger the formation of neurofibrillary tangles, a pathological hallmark of AD. mGluRs regulate neuronal injury and survival, possibly through a series of downstream protein kinase and cysteine protease signaling pathways that affect mitochondrially mediated programmed cell death. They may also play a role in glutamate-induced neuronal death by facilitating Cal(2+) mobilization. Hence, mGluRs have become a target for neuroprotective drug development. They represent a pharmacological path to a relatively subtle amelioration of neurotoxicity because they serve a modulatory rather than a direct role in excitatory glutamatergic transmission.

Distinct physiological mechanisms underlie altered glycinergic synaptic transmission in the murine mutants spastic, spasmodic, and oscillator

Spastic (spa), spasmodic (spd), and oscillator (ot) mice have naturally occurring glycine receptor ( GlyR) mutations, which manifest as motor deficits and an exaggerated startle response. Using whole-cell recording in hypoglossal motoneurons, we compared the physiological mechanisms by which each mutation alters GlyR function. Mean glycinergic miniature IPSC ( mIPSC) amplitude and frequency were dramatically reduced (> 50%) compared with controls for each mutant. mIPSC decay times were unchanged in spa/spa (4.5 +/- 0.3 vs 4.7 +/- 0.2 ms), reduced in spd/spd (2.7 +/- 0.2 vs 4.7 +/- 0.2 ms), and increased in ot/ot (12.3 +/- 1.2 vs 4.8 +/- 0.2 ms). Thus, in spastic, GlyRs are functionally normal but reduced in number, whereas in spasmodic, GlyR kinetics is faster. The oscillator mutation results in complete absence of alpha 1-containing GlyRs; however, some non-alpha 1-containing GlyRs persist at synapses. Fluctuation analysis of membrane current, induced by glycine application to outside-out patches, showed that mean single-channel conductance was increased in spa/spa (64.2 +/- 4.9 vs 36.1 +/- 1.4 pS), but unchanged in spd/spd (32.4 +/- 2.1 vs 35.3 +/- 2.1 pS). GlyR-mediated whole-cell currents in spa/spa exhibited increased picrotoxin sensitivity (27 vs 71% block for 100 mu M), indicating alpha 1 homomeric GlyR expression. The picrotoxin sensitivity of evoked glycinergic IPSCs and conductance of synaptic GlyRs, as determined by nonstationary variance analysis, were identical for spa/spa and controls. Together, these findings show the three mutations disrupt GlyR-mediated inhibition via different physiological mechanisms, and the spastic mutation results in compensatory alpha 1 homomeric GlyRs at extrasynaptic loci.