| Abstract No.: | B-B2028 |
| Country: | Canada |
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| Title: | NEUROPEPTIDE Y INHIBITS CALCIUM ELECTROGENESIS IN HUMAN AND RAT DENTATE GRANULE CELLS
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| Authors/Affiliations: | 1 Trevor Hamilton*; 1 William Colmers; 2 Matt Wheatley; 2 D.B. Sinclair;
1 University of Alberta, Edmonton, AB, Canada 2 University of Alberta Hospital, Edmonton, AB, Canada
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| Content: | Objective: Backpropagation evoked distal calcium currents are considered a powerful integrative mechanism used to associate simultaneous and/or high frequency input. In pyramidal neurons of neocortical layers 2/3 and 5, trains of somatic action potentials (APs) also travel antidromically into the dendritic tree. Activation of voltage-dependent calcium channels (VDCC) in the distal dendrite(s) can occur above a critical AP frequency, and result in a calcium-mediated, orthodromically-propagating depolarization, termed a backpropagation activated calcium current (BAC). BACs may have significant consequences for synaptic physiology, especially when appropriately timed with incoming input. Our objective was to study this integrative mechanism in rat and human dentate granule cells (DGCs) of the hippocampus. Specifically, we sought to determine whether trains of high-frequency backpropagating APs will evoke calcium electrogenesis, and if so, whether this activity is modulated by Neuropeptide Y (NPY).
Materials and Methods: Whole-cell, visualized-patch recordings were made in transverse hippocampal slices obtained from rat (300 μm thick) or human patients (350 μm) with intractable temporal lobe epilepsy. Our protocol evoked APs via square-pulse current injection (1 ms) from 1-5 nA at frequencies from 40-200 Hz, in 10 Hz increments. 4-aminopyridine (4-AP; 100 μM) was added to the bath solution to increase excitability and resulted in frequency-dependent afterdepolarizations (ADPs) observed at the soma. We calculated the ‘critical’ frequency’ (CF) by plotting the integral of the ADP against AP frequency, then determining the half-maximal value of the sharp rise in this integral. NPY (1 μM) and Cd2+ (50 μM) were applied via the bath unless otherwise indicated.
Results: In human and rat dentate granule cells, trains of somatic APs resulted in robust frequency-dependent ADPs in the presence of 4-AP. The average CF for human neurons (115.8 ± 6.23 Hz; n=14) was no different from rat DGCs (109.3 ± 2.7; n = 138). To determine whether VDCCs were involved, we applied Cd2+ (50 µM) and observed a complete inhibition of all frequency-dependent ADPs in both human (n = 4) and rat (n = 10) DGCs. Local application of Cd2+ (100 µM) to distal dendrites (n = 9), but not the proximal dendrites (n = 7) or soma (n = 10), resulted in a significant and reversible CF shift in rat DGCs, indicating that distal dendritic calcium influx is tuned to high-frequency input. Bath application of NPY (1 μM), previously reported to suppress voltage-dependent Ca2+ influx into the soma and dendrites of DGCs via inhibition of N-type VDCCs, shifted the CF to higher values in human (n = 6) and rat (n = 8) DGCs.
Conclusion: Dendrites of human and rat DGCs respond supra-linearly to high-frequency input. With 4-AP in the bath solution, trains of APs above a CF can activate distal VDCCs that result in robust somatic ADPs. These calcium-dependent potentials are modulated by the activation of NPY receptors. Thus, NPY can inhibit calcium channels on dendrites of DGCs and can thereby modulate the CF of BACs. |
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