The Journal of neuroscience : the official journal of the Society for Neuroscience
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The CNS is shielded from systemic influences by two separate barriers, the blood-brain barrier (BBB) and the blood-to-CSF barrier. Failure of either barrier bears profound significance in the etiology and diagnosis of several neurological diseases. Furthermore, selective opening of BBB tight junctions provides an opportunity for delivery of otherwise BBB impermeant drugs. ⋯ The time course of TTR extravasation was compared with release from the brain of another BBB integrity marker, S-100beta (11 kDa). Kinetic analysis revealed that the appearance of S-100beta, presumably originating from perivascular astrocytic end feet, preceded extravasation of TTR by several minutes. Because TTR is localized primarily in choroid plexus and, as a soluble monomer, in CSF, we concluded that although S-100beta is a marker of BBB integrity, TTR instead may be a peripheral tracer of blood-to-cerebrospinal barrier.
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To clarify the mechanism underlying improvement of parkinsonian signs by high-frequency electrical stimulation (HFS) of the subthalamic nucleus (STN), we investigated the effects of STN HFS on neuronal activity of the internal and external segment of the globus pallidus (GPi and GPe, respectively) in two rhesus monkeys rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. A scaled-down version of the chronic stimulating electrode used in humans, consisting of four metal contacts 0.50 mm in length each separated by 0.50 mm, was implanted through a cephalic chamber targeting the STN. Histological reconstruction revealed that the cathode was located in the STN in both monkeys. ⋯ Poststimulus time histograms of single neurons triggered by 2 Hz STN stimulation pulses at 2.4-3.0 V revealed short-latency excitations at 2.5-4.5 and 5.5-7.0 msec after stimulation onset and inhibitions at 1.0-2.5, 4.5-5.5, and 7.0-9.0 msec for both GPe and GPi neurons. These short-latency responses were present with 136 Hz stimulation, at voltages effective for alleviation of parkinsonian signs, resulting in a significant increase in mean discharge rate and a stimulus-synchronized regular firing pattern. These results indicate that activation of the STN efferent fibers and resultant changes in the temporal firing pattern of neurons in GPe and GPi underlie the beneficial effect of HFS in the STN in Parkinson's disease and further support the role of temporal firing patterns in the basal ganglia in the development of Parkinson's disease and other movement disorders.
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The effects of kainic acid (KA) on neurogenesis in the developing rat hippocampus were investigated. Neonatal [postnatal day (P) 7] rats received a single bilateral intracerebroventricular infusion of KA (50 nmol in 1.0 microl) or vehicle. At P14, P25, P40, and P60, the spatial and temporal relationships between the neurodegeneration and neurogenesis induced by KA were explored using terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) to detect the dying cells and 5-bromodeoxyuridine (BrdU) to label newly generated cells. ⋯ Newly generated cells in the CA3 subfield only rarely expressed glial markers (8%). These results suggest that a single exposure to KA at P7 has both immediate (inhibition) and delayed (stimulation) effects on neurogenesis within the dentate gyrus of developing rats. KA administration resulted in both neuronal apoptosis and neurogenesis within the CA3 subfield, suggesting that the purpose of neurogenesis in the CA3 is to replace neurons lost to apoptosis.
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Multiple trains of high-frequency synaptic stimulation evoke long-term potentiation (LTP) of synaptic transmission in hippocampal area CA1, which has been correlated with hippocampal long-term memory and requires the activation of cAMP-dependent protein kinase (PKA). To assess whether postsynaptic PKA is necessary for the expression of LTP, we made prolonged whole-cell voltage-clamp recordings from CA1 pyramidal neurons in mouse hippocampal slices during postsynaptic infusion of cell-impermeant modulators of PKA. Repeated stimulation (four 100 Hz trains at 5 min intervals) of the Schaffer collateral pathway increased synaptically evoked EPSCs for up to 2 hr. ⋯ The postsynaptic infusion of a constitutively active isoform of the PKA catalytic subunit (Calpha) into CA1 pyramidal neurons increased EPSC sizes to elicit long-lasting synaptic facilitation. Thus, mimicking the activation of PKA in postsynaptic CA1 pyramidal neurons is sufficient for inducing persistent synaptic facilitation. Activation of apostsynaptic PKA is necessary for the expression of LTP in CA1 pyramidal neurons and is sufficient for initiating persistent synaptic facilitation.
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Neuropathic pain is a common and often incapacitating clinical problem for which little useful therapy is presently available. Painful peripheral neuropathies can have many etiologies, among which are trauma, viral infections, exposure to radiation or chemotherapy, and metabolic or autoimmune diseases. Sufferers generally experience both pain at rest and exaggerated, painful sensitivity to light touch. ⋯ Nerve injury markedly increases pacemaker currents in large-diameter dorsal root ganglion neurons and results in pacemaker-driven spontaneous action potentials in the ligated nerve. Pharmacological blockade of HCN activity using the specific inhibitor ZD7288 reverses abnormal hypersensitivity to light touch and decreases the firing frequency of ectopic discharges originating in Abeta and Adelta fibers by 90 and 40%, respectively, without conduction blockade. These findings suggest novel insights into the molecular basis of pain and the possibility of new, specific, effective pharmacological therapies.