Neurobiology of disease
-
Neurobiology of disease · Sep 2012
Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA.
DYT1 dystonia, a common and severe primary dystonia, is caused by a 3-bp deletion in TOR1A which encodes torsinA, a protein found in the endoplasmic reticulum. Several cellular functions are altered by the mutant protein, but at a systems level the link between these and the symptoms of the disease is unclear. The most effective known therapy for DYT1 dystonia is the use of anticholinergic drugs. ⋯ Amphetamine stimulated dopamine release was also unaltered. These results demonstrate a cell-autonomous effect of Dyt1 deletion on striatal cholinergic function. Therapies directed at modifying the function of cholinergic neurons may prove useful in the treatment of the human disorder.
-
Neurobiology of disease · Sep 2012
Microglial inhibitory factor (MIF/TKP) mitigates secondary damage following spinal cord injury.
Spinal cord injury (SCI) induces an immune response during which microglia, the resident immunocompetent cells of the central nervous system, become activated and migrate to the site of damage. Depending on their state of activation, microglia secrete neurotoxic or neurotrophic factors that influence the surrounding environment and have a detrimental or restorative effect following SCI, including causing or protecting bystander damage to nearby undamaged tissue. Subsequent infiltration of macrophages contributes to the SCI outcome. ⋯ Moreover, timely inhibition of microglial/macrophage activation prevented demyelination and axonal dieback by modulating oligodendrocyte survival and oligodendrocyte precursor maturation. Microglia/macrophages located within or proximal to the lesion produced neurotoxic factors, such as tumor necrosis factor alpha (TNF-α). These results suggest that microglia/macrophages within the epicenter at early time points post injury are neurotoxic, contributing to demyelination and axonal degeneration and that MIF/TKP could be used in combination with other therapies to promote functional recovery.
-
Neurobiology of disease · Sep 2012
Activation of subthalamic alpha 2 noradrenergic receptors induces motor deficits as a consequence of neuronal burst firing.
The subthalamic nucleus (STN) plays a key role in the pathophysiology of Parkinson's disease. This was demonstrated by the fact that STN neurons express more bursts in animal models of the disease and by the ability of STN inactivation to alleviate motor deficits. However, the origin of the bursts and the causal link between STN bursts and motor deficits remain unknown. ⋯ In parallel, phenylephrine did not change locomotor activity. This is the first evidence showing the implication of α1-ARs in the modulation of firing rate and α2-ARs in the modulation of the firing pattern of STN neurons. Furthermore, our data provide also evidence that activation of the STN α2-ARs plays a key role in the genesis of subthalamic burst activity, which may be at the origin of motor deficits.
-
Neurobiology of disease · Jul 2012
Functional alterations in GABAergic fast-spiking interneurons in chronically injured epileptogenic neocortex.
Progress toward developing effective prophylaxis and treatment of posttraumatic epilepsy depends on a detailed understanding of the basic underlying mechanisms. One important factor contributing to epileptogenesis is decreased efficacy of GABAergic inhibition. Here we tested the hypothesis that the output of neocortical fast-spiking (FS) interneurons onto postsynaptic targets would be decreased in the undercut (UC) model of chronic posttraumatic epileptogenesis. ⋯ Assessment of the paired pulse ratio and presumed quantal release showed that there was a significant, but relatively modest, decrease in synaptic release probability and a non-significant reduction in quantal size. A reduced density of boutons on axons of biocytin-filled UC FS cells, together with a higher coefficient of variation of uIPSC amplitude in RS cells, suggested that the number of functional synapses presynaptically formed by FS cells may be reduced. Given the marked reduction in synaptic strength, other defects in the presynaptic vesicle release machinery likely occur, as well.
-
Neurobiology of disease · Jun 2012
ReviewCardiovascular dysautonomia in Parkinson disease: from pathophysiology to pathogenesis.
Signs or symptoms of impaired autonomic regulation of circulation often attend Parkinson disease (PD). This review covers biomarkers and mechanisms of autonomic cardiovascular abnormalities in PD and related alpha-synucleinopathies. The clearest clinical laboratory correlate of dysautonomia in PD is loss of myocardial noradrenergic innervation, detected by cardiac sympathetic neuroimaging. ⋯ Alpha-synucleinopathy in autonomic neurons may occur early in the pathogenetic process. The timing of cardiac noradrenergic denervation in PD is therefore a key issue. This review updates the field of autonomic cardiovascular abnormalities in PD and related disorders, with emphasis on relationships among striatal dopamine depletion, sympathetic noradrenergic denervation, and alpha-synucleinopathy.