Modulation of spontaneous hippocampal synaptic events with 5-hydroxyindole, 4OH-GTS-21, and rAAV-mediated alpha7 nicotinic receptor gene transfer.
One approach to treatment of negative cognitive effects associated with Alzheimer's disease and schizophrenia may involve activation of neuronal alpha7 nicotinic acetylcholine receptors (nAChRs). We used the alpha7-selective partial agonist 3-(4-hydroxy, 2-methoxy-benzylidene)anabaseine (4OH-GTS-21), the alpha7 modulator 5-hydroxyindole (5-HI), and recombinant adeno-associated virus (rAAV)-mediated alpha7 gene transfer in order to test the hypothesis whether combining these strategies would significantly increase indirect measures of alpha7 nAChR function, including measures of spontaneous synaptic events in CA1 pyramidal cells. 5-HI (1 mM), and 5-HI (1 mM)+4OH-GTS-21 (5 microM) increased the frequency of APV- and NBQX-sensitive currents, while 5-HI+4OH-GTS-21 increased the frequency and amplitude of bicuculline-sensitive currents. Effects on EPSCs were blocked with tetrodotoxin (TTX) (1 microM), but not by methyllycaconitine (MLA) (50 nM). Neither TTX nor MLA reduced the potentiation of IPSC frequencies. However, TTX blocked, and in some cases MLA reduced, the potentiation of IPSC amplitudes. These data suggest that effects of 5-HI+4OH-GTS-21 on EPSC frequency were associated with action potential-dependent transmitter release produced by 5HI, and that potentiation of IPSC amplitudes resulted at least in part, from activation of alpha7 nAChRs. Finally, rAAV-mediated alpha7 gene transfer did not alter the magnitude of effects produced by 5-HI or 5-HI+4OH-GTS-21. Thus, although we previously showed that direct measures of alpha7 nAChR function were enhanced by alpha7 gene transfer, indirect measures of alpha7 nAChRs function were not significantly enhanced by combining alpha7 gene transfer with either agonist activation or positive allosteric modulation of alpha7 nAChRs.