Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.148 (Thy1)
 1,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The widely held view that the pathophysiology of Parkinson's disease arises from an under-activation of the direct pathway striatal spiny neurons (dSPNs) has gained support from a recently described weakening of the glutamatergic projection from the parafascicular nucleus (PfN) to dSPNs in experimental parkinsonism. However, the impact of the remodeling of the thalamostriatal projection cannot be fully appreciated without considering its impact on cholinergic interneurons (ChIs) that themselves preferentially activate indirect pathway spiny neurons (iSPNs). To study this thalamostriatal projection, we virally transfected with Cre-dependent channelrhodopsin-2 (ChR2) the PfN of Vglut2-Cre mice that were dopamine-depleted with 6-hydroxydopamine (6-OHDA). In parallel, we studied the corticostriatal projection to ChIs in 6-OHDA-treated transgenic mice expressing ChR2 under the Thy1 promoter. We found the 6-OHDA lesions failed to affect short-term synaptic plasticity or the size of unitary responses evoked optogenetically in either of these projections. However, we found that NMDA-to-AMPA ratios at PfN synapses-that were significantly larger than NMDA-to-AMPA ratios at cortical synapses-were reduced by 6-OHDA treatment, thereby impairing synaptic integration at PfN synapses onto ChIs. Finally, we found that application of an agonist of the D5 dopamine receptors on ChIs potentiated NMDA currents without affecting AMPA currents or short-term plasticity selectively at PfN synapses. We propose that dopamine depletion leads to an effective de-potentiation of NMDA currents at PfN synapses onto ChIs which degrades synaptic integration. This selective remodeling of NMDA currents at PfN synapses may counter the selective weakening of PfN synapses onto dSPNs in parkinsonism.
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PMID:Selective remodeling of glutamatergic transmission to striatal cholinergic interneurons after dopamine depletion. 2892 4

Ubiquitin is an essential signaling protein that controls many different cellular processes. While cellular ubiquitin levels normally cycle between pools of free and conjugated ubiquitin, the balance of these ubiquitin pools can be shifted by exposure to a variety of cellular stresses. Altered ubiquitin pools are also observed in several neurological disorders, suggesting that imbalances in ubiquitin homeostasis may contribute to neuronal dysfunction. To examine the effects of increased ubiquitin levels on the mammalian nervous system, we generated transgenic mice that express ubiquitin under the control of the Thy1.2 promoter. While we did not detect global changes in levels of ubiquitin conjugates in the hippocampus, we found that increasing ubiquitin levels reduced AMPA (GRIA1-4) receptor expression without affecting the levels of NMDA (GRIN) or GABAA receptors. Ubiquitin over-expression also negatively impacted hippocampus-dependent learning and memory as well as baseline excitability and synaptic plasticity at hippocampal CA3-CA1 synapses. These changes occurred in a dose-dependent manner in that mice with the highest levels of ubiquitin over-expression had the greatest deficits in synaptic function and were the most impaired in the learning and memory tasks. As chronic elevation of ubiquitin expression in neurons is sufficient to cause changes in synaptic function and cognition, altered ubiquitin homeostasis may be an important contributor to the stress-induced changes observed in neurological disorders.
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PMID:Chronic over-expression of ubiquitin impairs learning, reduces synaptic plasticity, and enhances GRIA receptor turnover in mice. 3045 Dec 89