The Effects Of α7nAChR And α4β2nAChR On CA3Pyramidal Neurons Or DG Granule Cells And Their Mechanisms

Nicotinic acetylcholine receptors (nAChRs) are important neuronal transmitter receptors and widely expressed in central nervous system. It is well known that cholinergic system takes part in several important brain functions, such as attention, learning, arousal and cognition, and is also closely related to Alzheimer’s disease, Parkinson’s disease, schizophrenia and some other nervous system diseases. nAChRs are anion channels and exist as multiple, diverse subtypes composed as pentamers of different types of subunits with unique property, function and distribution. nAChRs that exist in brain are composed of α-α10and β2-β4subunits. Among all the nAChR subtypes, homomeric a7and the heteromeric α4β2receptors are most wildly and highly expressed nAChR subtypes throughout the central nervous system. Many evidences support that nicotine and nAChRs are closely related with learning and memory. Several behavior and hippocampus electrophysiological studies have shown that α7and α4β2receptors play important roles in cognition. Long-term potentiation (LTP) in hippocampus is thought to be the cellular model of learning and memory. Several studies have shown that application of agonist and antagonist of α7and α4β2receptors can affect LTP in hippocampus but the mechanisms of these effects are not clear yet. In the first part of our study, single-cell extracellular recordings were made in vivo to study the effects of nicotine or a7selective agonists, AR-R17779and PSAB-OFP, applied systemically or iontophoretically, on CA3pyramidal neurons in hippocampus. The results show that either systemically or iontophoretically application of nicotine or α7receptor agonists increased the firing rate in most neurons recorded and these effects could be inhibited by a7receptor selective antagonist MLA. Iontophoretical studies shows that the excitation evoked by α7receptor agonists was eliminated by co-iontophoretic application of either DNQX or D-AP5, the selective NMDA and non-NMDA receptor antagonists, respectively. These results suggest that CA3pyramidal neurones are modulated by activation of presynaptic α7nicotinic receptors, which, at least in part, enhances glutamate release onto post-synaptic AMPA and NMDA receptors on these CA3neurons. In the second part of our study, α4β2receptor selective partial agonist TC-2559was applied on DG granule cells by puff application in hippocampal slice preparations. These results show that application of TC-2559reduced the frequency of sEPSCs in granule cells but had no effect on the mEPSCs, and GABAA receptor antagonist bicuculline inhibited the effect of TC-2559. These results suggest that the activation of α4β2receptor inhibits presynaptic glutamate release on granule cells, moreover, a polysynaptic mechanism and a GABAergic interneuron’s role is likely involved in this action.