Abstracts

Rationale: 5-HT6 receptor antagonists have been shown to have anti-seizure activity and improve cognitive performance. Accordingly, these compounds are being advanced as safe treatments for cognitive dysfunction. However, 5-HT6 antagonists have not been tested in transgenic animal models of disease where their effects may be different than those observed in healthy nontransgenic (NTG) animals. One such model, the J20 human Amyloid Precursor Protein (hAPP) mouse model of Alzheimer disease (AD), has spontaneous seizures, remodeled GABAergic interneurons, and altered synaptic inhibition in the dentate gyrus (DG). Remodeling of inhibitory networks in response to seizures is a common feature in animal models of epilepsy, as well as AD, which may contribute to cognitive dysfunction. Thus, the effects of a representative 5-HT6 antagonist on inhibitory postsynaptic currents (IPSCs) were compared in DG granule cells (GCs) from J20 and NTG mice.Methods: Coronal brain slices containing the dorsal hippocampus were made from either J20 mice or their NTG littermates. Evoked and spontaneous IPSCs (eIPSCs & sIPSCs) were recorded from voltage clamped GCs. Slices were sequentially exposed to serotonin (5-HT, 1 M) + fluoxetine (10 M), and then in combination with the 5-HT6 receptor antagonist SB-399885 (1 M). An unpaired, two-tailed, Student s t test was used to compare parameters between J20 and NTG mice, and a one-way repeated measures ANOVA, with Tukey s multiple comparison test, was used to compare the effects of drug treatments.Results: Membrane resistance (Rm) was significantly greater in J20 mice (428.4 44.1 M , N=10) than in NTG littermates (310.8 25.1 M , N=13). Otherwise, baseline electrophysiological characteristics were similar between J20 and NTG mice. There was a significant effect of drug treatments on Rm [F(2,9)=4.2, p=0.03] and eIPSC paired pulse ratio [F(2,8)=5.0, p=0.02] in J20 mice only; in 5-HT + Fluoxetine, Rm (562.7 81.2 M ) was significantly increased and paired-pulse depression (91.6 33.3%) was significantly different than baseline (62.3 6.5%). In the presence of SB-399885, both parameters were not significantly different than baseline measurements. Finally, there was a significant increase in inter-event interval (IEI) of sIPSCs [F(2,10)=3.6, p=0.04] in NTG mice only; mean IEI in 5-HT + fluoxetine (380.4 32.4 ms) was significantly different than the IEI in 5-HT + Fluoxetine + SB-399885 (495.8 65.1 ms).Conclusions: These results demonstrate that, in J20 mice only, the Rm of GCs robustly increases, and eIPSC paired-pulse depression decreases, in response to 5-HT and fluoxetine, and these effects are reversed by the 5-HT6 antagonist SB-399885. However, SB-399885 significantly increases the sIPSC IEI in NTG mice only. These results suggest that 5-HT6 antagonists have effects on GCs and interneurons in J20 mice that are substantially different than those observed in otherwise healthy NTG animals. This project was funded by the Epilepsy Foundation.