Neuroscience
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Absence seizures arise from disturbances within the corticothalamocortical network, however the precise cellular and molecular mechanisms underlying seizure generation arising from different genetic backgrounds are not fully understood. While recent experimental evidence suggests that changes in inhibitory microcircuits in the cortex may contribute to generation of the hallmark spike-wave discharges, it is still unclear if altered cortical inhibition is a result of interneuron dysfunction due to compromised glutamatergic excitation and/or changes in cortical interneuron number. The stargazer mouse model of absence epilepsy presents with a genetic deficit in stargazin, which is predominantly expressed in cortical parvalbumin-positive (PV(+)) interneurons, and involved in the trafficking of glutamatergic AMPA receptors. ⋯ Further analysis using confocal fluorescence microscopy revealed that although there are no changes in cortical PV(+) interneuron number, there is a predominant loss of GluA1 and 4 containing AMPA receptors in PV(+) neurons in stargazers compared to non-epileptic controls. Taken together, these data suggest that the loss of AMPA receptors in PV(+) neurons could impair their feed-forward inhibitory output, ultimately altering cortical network oscillations, and contribute to seizure generation in stargazers. As such the feed-forward inhibitory interneurons could be potential targets for future therapeutic intervention for some absence epilepsy patients.
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Parkinson's disease (PD) is a neurodegenerative disease caused by a gradual loss of midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SNpc) during aging. 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is one of the neurotoxins used widely to induce PD-like symptoms in PD animal models, including rodents and non-human primates. It has been reported that deletion of autophagy-related gene 7 (Atg7) in the brain results in a reduction of mDA neurons in adulthood. In this study, we used tyrosine hydroxylase (TH)-Cre mice to generate conditional knockout (CKO) mice with the specific deletion of Atg7 in mDA neurons. ⋯ TH-expressing neurons containing puncta-like structures with p62 and ubiquitin immunoreactivity were observed in the midbrain of Atg7 CKO mice but were not detected in control mice. However, MPTP-induced loss of mDA neurons was not observed in Atg7 CKO mice. Our results indicate that Atg7-involved autophagy is required not only for the survival of mDA neurons in the mouse brain, but also for MPTP-induced mDA neuron degeneration.
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Propofol is a major intravenous anesthetic that facilitates GABAA receptor-mediated inhibitory synaptic currents and modulates inward current (Ih), K(+), and voltage-gated Na(+) currents. This propofol-induced modulation of ionic currents changes intrinsic membrane properties and repetitive spike firing in cortical pyramidal neurons. However, it has been unknown whether propofol modulates these electrophysiological properties in GABAergic neurons, which express these ion channels at different levels. ⋯ Using a low concentration of propofol clarified this tendency: 30μM propofol decreased the firing of pyramidal neurons but had little effect on GABAergic neurons. Pre-application of a GABAA receptor antagonist, picrotoxin (100μM), diminished the propofol-induced suppression of neural activities in both pyramidal and FS neurons. These results suggest that GABAergic neurons, especially FS neurons, are less affected by propofol than are pyramidal neurons and that propofol-induced modulation of the intrinsic membrane properties and repetitive spike firing are principally mediated by GABAA receptor-mediated tonic currents.
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The frequency of intrusive saccades during maintenance of active visual fixation has been used as a measure of sustained visual attention in studies of healthy subjects as well as of neuropsychiatric patient populations. In this study, the mechanism that generates intrusive saccades during active visual fixation was investigated in a population of young healthy men performing three sustained fixation tasks (fixation to a visual target, fixation to a visual target with visual distracters, and fixation straight ahead in the dark). Markov Chain modeling of inter-saccade intervals (ISIs) was utilized. ⋯ Accordingly, the system of intrusive saccade generation may operate in two "attractor" states, one in which intrusive saccades occur at short consecutive ISIs and another in which intrusive saccades occur at long consecutive ISIs. These states might correspond to two distinct states of the attention system, one of low focused - high distractibility and another of high focused - low distractibility, such as those proposed in the adaptive gain theory for the control of attention by the noradrenergic system in the brain. To the authors knowledge, this is the first time that Markov Chain modeling has been applied to the analysis of the ISIs of intrusive saccades.
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Thrombin and activated protein C (aPC) bound to the endothelial protein C receptor (EPCR) both activate protease-activated receptor 1 (PAR1) generating either harmful or protective signaling respectively. In the present study we examined the localization of PAR-1 and EPCR and thrombin activity in Schwann glial cells of normal and crushed peripheral nerve and in Schwannoma cell lines. In the sciatic crush model nerves were excised 1h, 1, 4, and 7days after the injury. ⋯ EPCR was found to be located at the microvilli of Schwann cells at the node of Ranvier and in cytoplasm surrounding the nucleus. Four days after sciatic injury, EPCR levels increased significantly (57,785±16602AU versus 4790±1294AU in the contralateral uninjured nerves, p<0.001 by t-test) mainly distal to the site of injury, where axon degeneration is followed by proliferation of Schwann cells which are diffusely stained for EPCR. EPCR seems to be located to cytoplasmic component of Schwann cells and not to compact myelin component, and is highly increased following injury.