Abstracts

We present initial results of a combined experimental and computational modeling study of how the anatomical and biophysical properties of mossy cells (MCs) and their synaptic inputs may affect their function in temporal lobe epilepsy (TLE) and learning. Situated in the hippocampal hilus, MCs receive two principal excitatory projections: a major input via mossy fibers (MFs) from dentate gyrus (DG) granule cells, and a lesser input via collateral (CL) axons from CA3 pyramidal cells. MF boutons are complex and synapse onto similarly complex spines called thorny excrescences located [lang]100 [micro]m of the MC soma. CL axons attach to distal , more simple spines. Induction of TLE is associated with loss of many MCs and an increased relative abundance and amplitude of CL EPSPs. To understand the implications of these changes, it is necessary to determine how the properties of MCs and their excitatory inputs affect synaptic integration. Of particular interest are the functional consequences of the spatial distribution (proximal vs. distal) and anatomical specializations (thorns vs. spines) of MF and CL inputs. We simulated anatomically complex multicompartmental models using NEURON (Hines [amp] Carnevale 2001). Pending availability of detailed MC morphometric data, our model was based on measurements of a CA3 neuron by David Amaral (see http://www.krasnow.gmu.edu/L-Neuron (Ascoli et al., 2001)). Specific Cm and Rm were adjusted to match the model to our measurements of MC input resistance and membrane time constant. We performed three families of simulations in which the soma was voltage clamped while a synapse (based on our mEPSC measurements from MCs) was marched over all dendritic compartments within 100 [micro]m of the soma: control (synapse attached directly to dendritic shaft, clamp series resistance (Rclamp) 0); test 1 (synapse attached to the distal head of a complex thorn (Chicurel [amp] Harris 1992)); test 2 (Rclamp 10 M[Omega]). In all cases, the largest EPSCs corresponded to the most proximal locations, and the fastest EPSCs suffered the least attenuation. Uncompensated Rclamp produced strong attenuation of peak EPSC amplitude, but less increase in the rise time and decay time. Distance from the soma had little effect on rise time and amplitude for the first 30 [micro]m. The thorn reduced EPSC amplitude by a few percent, most noticable in the largest EPSCs.
The largest events in our experimental data appeared to come from proximal locations, as they can be evoked by focal application of high sucrose near the soma (Livsey [amp] Vicini 1992). However, they were not the fastest events but had relatively slow rise and decay times. We applied deconvolution analysis (Diamond [amp] Jahr, 1995) and found that asynchronous release might account for this unexpected result. These results suggest that the largest EPSCs in MCs may actually be generated by asynchronous transmitter release, possibly occurring at multiple active zones on large thorns. (Supported by NIH)