Neuroscience
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Neurofibromatosis type I is a common autosomal dominant disease characterized by formation of multiple benign and malignant tumors. People with this disorder also experience chronic pain, which can be disabling. Neurofibrinomin, the protein product of the NF1 gene (neurofibromin gene (human)), is a guanosine triphosphate activating protein for p21(ras). ⋯ When nerve growth factor was removed 48 h before conducting release experiments, nerve growth factor-induced augmentation of immunoreactive calcitonin gene-related peptide release from Nf1+/- neurons was more pronounced than in Nf1+/- sensory neurons that were treated with nerve growth factor continuously for 5-7 days. Thus, sensory neurons from mice with a heterozygous mutation of the Nf1 gene that is analogous to the human disease neurofibromatosis type I, exhibit increased sensitivity to chemical stimulation. This augmented responsiveness may explain the abnormal pain sensations experienced by people with neurofibromatosis type I and suggests an important role for guanosine triphosphate activating proteins, in the regulation of nociceptive sensory neuron sensitization.
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The expression of Kv3.1 and Kv3.2 voltage-gated potassium channel subunits appears to be critical for high-frequency firing of many neuronal populations. In the cortex these subunits are mainly associated with fast-firing GABAergic interneurons containing parvalbumin or somatostatin. Since the basolateral nuclear complex of the amygdala contains similar interneurons, it is of interest to determine if these potassium channel subunits are expressed in these same interneuronal subpopulations. ⋯ These Kv3.2-containing somatostatin+ interneurons constituted 27-50% of the somatostatin+ population, depending on the nucleus in question. These data suggest that both fast-firing and burst-firing parvalbumin+ interneurons in the basolateral amygdala express the Kv3.1b subunit. The significance of Kv3.2 expression in some parvalbumin+ and somatostatin+ interneurons remains to be determined.
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It has been reported recently that mice lacking both alleles of the LIM-homeobox gene Lhx7, display dramatically reduced number of forebrain cholinergic neurons. In the present study, we investigated whether the Lhx7 mutation affects male and female mice differently, given the fact that gender differences are consistently observed in forebrain cholinergic function. Our results show that in adult male as well as female Lhx7 homozygous mutants there is a dramatic loss of choline acetyltransferase immunoreactive forebrain neurons, both projection and interneurons. ⋯ Furthermore, there was an increase of M1-, but not M2-, muscarinic acetylcholine receptor binding site density in the somatosensory cortex and basal ganglia of only the female homozygous mutant mice. Such an increase can be regarded as a mechanism acting to compensate for the dramatically reduced cholinergic input, raising the possibility that the forebrain cholinergic system in female mice may be more plastic and responsive to situations of limited neurotransmitter availability. Finally, our study provides additional data for the sexual dimorphism of the forebrain cholinergic system, as female mice appear to have a lower density of M1-muscarinic acetylcholine receptors in the striatal areas of the basal ganglia and a higher density of M2-muscarinic acetylcholine receptors, in a number of cortical areas, as well as the striatal areas of the basal ganglia.
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The angiotensin 4 receptor (AT4) subtype is heavily distributed in the dentate gyrus and CA1-CA3 subfields of the hippocampus. Neuronal pathways connecting these subfields are believed to be activated during learning and memory processing. ur laboratory previously demonstrated that application of the AT4 agonist, Norleucine1-angiotensin IV, enhanced baseline synaptic transmission and long-term potentiation, whereas perfusion with the AT4 antagonist, Norleucine1-Leu3-psi(CH2-NH2)3-4-angiotensin IV disrupted long-term potentiation stabilization in area CA1. The objective of the present study was to identify the mechanism(s) responsible for Norleucine1-angiotensin IV-induced increase in hippocampal long-term potentiation. ⋯ In support of this notion the application of Nle1-angiotensin IV to cultured rat hippocampal neurons resulted in increased intracellular calcium derived exclusively from extracellular sources. Consistent with these observations Nle1-angiotensin IV was capable of augmenting the uptake of 45Ca2+ into rat hippocampal slices. Taken together, these data indicate that increased calcium influx through postsynaptic calcium channels contribute to Norleucine1-angiotensin IV-induced enhancement of long-term potentiation.
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Changes in the signaling of wide dynamic range neurons and the expression of glutamate transporters in the lumbar spinal dorsal horn of rats with Taxol-induced hyperalgesia are detailed in this report. Deep spinal lamina neurons have significantly increased spontaneous activity and after-discharges to noxious mechanical stimuli, increased responses to both skin heating and cooling, and increased after-discharges and abnormal windup to transcutaneous electrical stimuli. ⋯ These results suggest a state of increased excitability develops in spinal pain-signaling neurons as a consequence of decreased glutamate clearance. These changes in dorsal horn neurobiology likely in turn contribute to the hyper-responsiveness to sensory stimuli seen in animals treated with Taxol and may play a role in the pain seen in cancer patients receiving Taxol.