ABSTRACT
Amyloid aggregates of the protein α-synuclein (αS) called Lewy Bodies (LB) and Lewy Neurites (LN) are the pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. We have previously shown that high extracellular αS concentrations can be toxic to cells and that neurons take up αS. Here we aimed to get more insight into the toxicity mechanism associated with high extracellular αS concentrations (50-100 µM). High extracellular αS concentrations resulted in a reduction of the firing rate of the neuronal network by disrupting synaptic transmission, while the neuronal ability to fire action potentials was still intact. Furthermore, many cells developed αS deposits larger than 500 nm within five days, but otherwise appeared healthy. Synaptic dysfunction clearly occurred before the establishment of large intracellular deposits and neuronal death, suggesting that an excessive extracellular αS concentration caused synaptic failure and which later possibly contributed to neuronal death.
Subject(s)
Cerebral Cortex/metabolism , Neurons/metabolism , Synapses/metabolism , Synaptic Transmission/physiology , alpha-Synuclein/metabolism , Action Potentials/drug effects , Action Potentials/physiology , Animals , Cell Survival/drug effects , Cell Survival/physiology , Cells, Cultured , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Extracellular Space/drug effects , Extracellular Space/metabolism , Humans , Intracellular Space/drug effects , Intracellular Space/metabolism , Neurons/drug effects , Neurons/pathology , Protein Aggregation, Pathological/pathology , Rats, Wistar , Recombinant Proteins/administration & dosage , Recombinant Proteins/metabolism , Recombinant Proteins/toxicity , Synapses/drug effects , Synaptic Transmission/drug effects , alpha-Synuclein/administration & dosage , alpha-Synuclein/toxicityABSTRACT
There is little information about neurotrophic regulation in the developing rat hypothalamus. In the present study, we therefore examined the expression of neurotrophin receptor TrkC in the developing forebrain and hypothalamus. In situ hybridization of coronal sections revealed that on the 15th day of gestation, trkC messenger RNA expression is homogeneously distributed over the neocortex, septum, thalamus, hypothalamus, hippocampus, rhinencephalon and the amygdala. Exceptions were the anteroventral nucleus of the hypothalamus and the striatum, which showed higher levels of trkC messenger RNA expression, and the germinal zones which were devoid of trkC messenger RNA. After birth, the homogeneous staining pattern changes into a heterogeneous staining pattern like that found in adulthood. TrkC expression is observed in the area of the suprachiasmatic nucleus as early as E17 and continues until adulthood. The presence of the TrkC receptor in the E17 suprachiasmatic nucleus suggests that neurotrophin-3 plays a role in development of this structure and that application of neurotrophin-3 could stimulate neuronal survival and neuritic outgrowth in a suprachiasmatic nucleus transplantation model.
