br Acknowledgments This work was

Acknowledgments This work was supported by the R&D Program of the Institutional Research Program of KRICT (SI1701-02), and by the Next generation carbon upcycling project of Ministry of Science and ICT. JSC is kindly grateful to the National Research Council of Science and Technology (NST) for financial support (KN16-15). This work was also supported by the Mid-career Researcher Support Program through the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future planning (MSIP) of Korea (No. 2015R1A2A1A01005393).
Introduction The α7 subtype of nicotinic DRB receptor (nAChR) has long been considered a potential therapeutic target for treating cognitive disorders, and α7-selective drugs have been shown to be effective at improving baseline or compromised behavior in animal models of learning and memory [5], [13], [27], [45], [51], [53], [55]. Drugs targeting α7 have also been identified as effective at reducing inflammation and associated pain [43], [47]. While α7 channel activation appears to be important for cognitive effects [8], it does not seem to be important for the modulation of inflammation [4], [26], [49], [54]. In fact, NS6740, which is a compound with good activity in models of inflammation and pain, is an extremely weak partial agonist of α7 and is otherwise a strong desensitizer of α7 channel activity [32]. NS6740 is, however, able to activate large α7 ion channel currents in the presence of a positive allosteric modulator (PAM), identifying it as a “silent agonist”. The concept that there are two distinct types of α7-mediated signaling is supported by reports that NS6740 is not only ineffective in cognitive tests, it is able to block the effects of cognition-enhancing α7 channel activators, for example, the effects of the α7 agonist BMS-902483 on improving novel object recognition [44]. On its own, BMS-902483 has been also shown to increase hippocampal long-term potentiation (LTP), an effect hypothesized to be related to its positive cognitive effects. LTP is arguably the most widely accepted neurophysiological correlate of learning and memory, involving long-lasting change in synaptic efficacy, which can be experimentally induced by high-frequency stimulation (HFS) of presynaptic axons. Mechanisms that have been shown to be important for LTP have also been demonstrated essential for spatial learning [28], [41], fear conditioning [48], and passive avoidance learning [60]. LTP in the dentate gyrus of the hippocampus has been reported to be enhanced by acute application of nicotine [59]. This effect was reportedly blocked by methyllycaconitine (MLA) and absent in α7 nAChR knockout mice. However, other nAChR, including heteromeric α2β2 receptors, have also been implicated in the induction and modulation of hippocampal LTP [30], [31]. Here we report the effects of NS6740 on synaptic function and plasticity in the dentate gyrus of the rat hippocampus. Using heterologously expressed receptors, we investigated the effects of NS6740 on several ion channel receptors associated with synaptic function in the hippocampus, including important subtypes of AMPA-sensitive glutamate receptors, GABAA receptors, and α2β2 subtypes of nAChR.
Methods and materials
Results
Discussion Our experimental design was based the methods described by Welsby et al. [59], who previously reported that 5 μM nicotine produced a robust enhancement of dentate LTP, with an early potentiation of 250% compared to a control of 200%, and increase at 60 min after HFS of 182% compared to 143% in the control slices. Although we saw significant LTP under all conditions (P < 0.05), we observed lower levels of LTP under control conditions and no significant effects of 5 or 10 μM nicotine compared to controls. It should be noted that nicotine is a very non-selective agonist and at concentrations greater than 1 μM would predominantly desensitize all heteromeric nAChR [40]. Likewise, at such concentrations nicotine would produce only very transient activation of α7 nAChR and virtually no steady-state currents [35], [40].