Neuroscience
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Glial cell line-derived neurotrophic factor is one of the most potent motoneuron survival factors yet identified. Although retrograde transport of trophic factors to the cell body is thought to be an important process in motoneuron survival, the transport pathways that lead to interaction of glial cell line-derived neurotrophic factor with its receptors is not known. We have used a double ligated hypoglossal nerve preparation to investigate transport of endogenous glial cell line-derived neurotrophic factor and its receptors, glial cell line-derived neurotrophic factor family receptor alpha1 and receptor re-arranged during transfection. ⋯ Our results indicate anterograde transport of Schwann cell-derived glial cell line-derived neurotrophic factor, which is dependent on binding to its cell body-derived receptors. These findings suggest a mechanism for collection of glial cell line-derived neurotrophic factor from multiple Schwann cells which surround motor axons. We propose that in addition to its role in motoneuron survival, glial cell line-derived neurotrophic factor may also modulate local neuronal effects in distal regions of the nerve.
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We examined the acute expression of c-Fos or Zif/268 by simultaneous activation of N-methyl-D-aspartate receptor and neurokinin-1 receptor of the trigeminal nucleus caudalis in anesthetized rats. A selective N-methyl-D-aspartate receptor agonist, N-methyl-D-aspartate, and/or a selective neurokinin-1 receptor agonist, substance P, was applied topically to the dorsal surface of the spinal trigeminal tract. Immunohistochemically stained nuclei for c-Fos and Zif/268 at laminae I and II of the trigeminal nucleus caudalis were counted. ⋯ Other combinations did not increase c-Fos and Zif/268. Our results indicate that activation of N-methyl-D-aspartate or neurokinin-1 receptor of the trigeminal nucleus caudalis contributes to the acute induction of both c-Fos and Zif/268 on the ipsilateral superficial layer of this nucleus and simultaneous activation of both receptors by their agonists with specific concentrations produces a marked expression of these proteins. Simultaneous activation of N-methyl-D-aspartate and neurokinin-1 receptors under some specific conditions may augment synaptic transmission, contributing to long-term neuronal change.
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In transgenic mice expressing ectopic substance P fibres in the spinal white matter, a normally innocuous mechanical stimulus induces hyperalgesia and allodynia which are reversed by substance P and N-methyl-D-aspartate receptor antagonists. This period of enhanced excitation is followed by a rebound overshoot in these animals. As previous evidence indicates opioid mechanisms in a similar rebound in normal animals, the present study was done to determine the effects of systemic administration of morphine and the opiate receptor antagonist, naloxone, on the stimulus-induced responses in the tail withdrawal reflex. ⋯ This is a novel observation because the genetic manipulation in this transgenic mouse results in a transient over-expression of nerve growth factor during development that leads to the formation of ectopic primary afferent fibres in the spinal cord containing substance P. These fibres persist indefinitely after the nerve growth factor levels return to normal. Opioid mechanisms, which are likely of dorsal horn origin, do not fall under the direct influence of nerve growth factor mechanisms and therefore the intriguing possibility is raised that opioid mechanisms in the spinal cord are regulated at least in part by substance P-related mechanisms.
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Effects of cholinergic agents on synaptic transmission and plasticity were examined in entorhinal cortex and hippocampus. Bath application of carbachol (0.25-0.75 microM) induced transient depression of field potential responses in all cases tested (24/24 in layer III of medial entorhinal cortex slices and 24/24 in CA1 of hippocampal slices; 11.0+/-1.9% and 7.8+/-2.5%, respectively) and long-lasting potentiation in some cases (4/24 in entorhinal cortex and 12/24 in hippocampus; 33.7+/-3.7% and 32.1+/-9.9%, respectively, in successful cases). Carbachol (0.5 microM) induced transient depression, but not long-lasting potentiation, of N-methyl-D-aspartate receptor-mediated responses in entorhinal cortex. ⋯ Long-term potentiation could be induced in the presence of 10 microM atropine by theta burst stimulation. The magnitude was significantly lower (15.2+/-5.2%, n=9) compared with control (37.2+/-6.1%, n=8) in entorhinal cortex, however. These results demonstrate similar, but not identical, cholinergic modulation of synaptic transmission and plasticity in entorhinal cortex and hippocampus.
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Whole-cell patch-clamp techniques were used to study the effects of nerve growth factor on voltage-dependent potassium conductance in normal and axotomized identified large cutaneous afferent dorsal root ganglion neurons (48-50 micrometer diameter) many of which probably give rise to myelinated Abeta fibers. K-currents were isolated by blocking Na- and Ca-currents with appropriate ion replacement and channel blockers. Separation of current components was achieved on the basis of response to variation in conditioning voltage. ⋯ Nerve crush, which allows regeneration to peripheral targets and exposure of the regenerating nerve to the distal nerve segment, resulted in a small reduction in sustained K-current but no reduction in transient A-current compared to controls. Levels of transient A-current and sustained K-current were maintained at control levels after nerve growth factor treatment. These results indicate that the large reduction in transient A-current, and in sustained K-current, observed in cutaneous afferent cell bodies after nerve ligation is prevented by application of nerve growth factor.