| Abstract No.: | B-B2072 |
| Country: | Canada |
| | |
| Title: | ELECTROPHYSIOLOGICAL EFFECTS OF PRION PROTEIN PEPTIDE (PRP106-126) ON THE RAT BASAL FOREBRAIN NEURONS |
| | |
| Authors/Affiliations: | 1 Kwai Alier*; 1 David MacTavish; 1 Zongming Li; 1 Jack Jhamandas;
1 University of Alberta, Edmonton, AB, Canada
|
| | |
| Content: | Objectives: Prion diseases (transmissible spongiform encephalopathies) are neurodegenerative disorders that affect a variety of species and are characterized by the presence of the misfolded prion protein (PrP). The neurotoxic effects of PrP may result from PrP-induced modulation of ion channel function, changes in neuronal excitability and consequent disruption of cellular homeostasis. We therefore examined the effects of PrP on a suite of potassium (K+) conductances that govern excitability of rat basal forebrain neurons. Our study examined the effects of a PrP fragment (Prp106-126, 50nM) on rat basal forebrain neurons using the patch clamp technique.
Material and Methods: Whole-cell recordings were obtained from acutely dissociated neurons of the diagonal band of Broca (DBB), a basal forebrain nucleus. We used single cell RT-PCR to establish the chemical phenotype of DBB cells (i.e. cholinergic versus GABAergic), and we further examined cells for expression of the Kv4.2 channel.
Results: Our results indicate PrP106-126, but not the scrambled sequence of PrP106-126, evokes a reduction of whole-cell outward currents in a voltage range between -30 and +30 mV. PrP106-126 inhibited peak whole-cell currents in DBB neurons in a concentration-dependent (1nM-30 µM) manner with an EC50 of 85 nM. The reduction of whole cell outward-currents evoked by PrP106-126 was significantly attenuated in Ca2+-free external media and also in the presence of iberiotoxin, a blocker of calcium-activated potassium conductance (Ic or BK channels). PrP application also evoked a depression of the delayed rectifier (IK) and transient outward (IA) potassium currents. Using single cell RT-PCR, we identified the presence of two neuronal chemical phenotypes, GABAergic and cholinergic, in cells that we recorded from. Furthermore, some GABAergic neurons were shown to express Kv4.2 channels.
Conclusion: Our data suggests that the PrP106-126 induces a reduction of specific K+ channel conductances in basal forebrain neurons and such changes have been previously demonstrated to result in an overall increased excitability of these neurons. The downstream effects of these cellular changes include increased calcium entry into cells and an activation of apoptotic pathways resulting in cell death.
This project was supported by Alberta Prion Research Institute and the Alberta Ingenuity Fund
|
| | |
| Back |
|
