Multiple forms of synaptic plasticity have previously been shown to be regulated by both nAChR and mAChR activation. For the nAChRs (and in particular the α7 subtype), the activation of receptors with exogenous ligands in the CA1 and dentate regions enhanced synaptic plasticity (Fujii et al., 1999
; Mann and Greenfield, 2003
; Welsby et al., 2006
; Welsby et al., 2007
). Furthermore the effect that the activation of these receptors has on synaptic plasticity can depend on the location of the receptors as well as timing; for example, the activation of α7 nAChRs on hippocampal interneurons can block concurrent STP and LTP in pyramidal cells, whereas presynaptic nAChRs can enhance the release of glutamate and thus increase the probability of inducing LTP (Ji et al., 2001
). In addition exogenous ACh may convert HFS-induced STP to LTP or LTD, depending on the timing relative to the SC stimulation (Ge and Dani, 2005
). Our current study is in large part consistent with these conclusions, stressing the importance of proper timing of cholinergic activation in shaping hippocampal synaptic plasticity. We have also recently shown that nicotine, acting through the non-α7 nAChRs, was able to enhance synaptic plasticity in deep layers of the entorhinal cortex (Tu et al., 2009
). This is consistent with a recent report that α4-containing nAChRs contribute to LTP facilitation in the perforant path (Nashmi et al., 2007
). Multiple forms of synaptic plasticity can also be regulated by mAChRs (Maylie and Adelman, 2010
). For example, the activation of presynaptic or postsynaptic mAChRs has previously been shown to either enhance or reduce LTP in the hippocampus (Leung et al., 2003
; Ovsepian et al., 2004
; Seeger et al., 2004
; Cobb and Davies, 2005
). Recently it was shown that endogenous ACh, acting through the M1 mAChR subtype, facilitates LTP in the hippocampus via inhibition of SK channels (Buchanan et al., 2010
Here we show that the septal cholinergic input can directly induce hippocampal synaptic plasticity in a timing-dependent manner. When the cholinergic input to the CA1 was activated 100 msec or 10 msec prior to the SC stimulation, it resulted in α7 nAChR-dependent LTP or STD, respectively. This α7 nAChR-dependent LTP was likely due to a postsynaptic effect that required the activation of the NMDAR and prolongation of the NMDAR-mediated calcium transients in the spines, and GluR2-containing AMPAR synaptic insertion. The α7 nAChR-dependent STD appears to be mediated primarily through the presynaptic inhibition of glutamate release (). The third and last form of plasticity that we observed was when the cholinergic stimulation was given 10 msec after the SC stimulation; this induced LTP that was dependent on the activation of the mAChR. The underlying mechanism is not clear at this time. PPR study suggests a postsynaptic mechanism (), but we have not been able to block this LTP with a calcium chelator dialyzed into the cells under recording (data not shown).
The majority of modulatory transmitter receptors are G-protein coupled receptors which exert functions through intracellular signaling pathways, and are thus considered slow synaptic transmission mediators, as opposed to those receptors that are ligand gated ion-channels (Greengard, 2001
). Previous studies have focused on the modulatory effects on existing HFS-induced hippocampal synaptic plasticity by either nAChR or mAChR activation. Our study here clearly shows that cholinergic input, through either its ion channel receptor (α7 nAChR) or the G protein-coupled receptor (mAChR), can directly induce hippocampal synaptic plasticity in a timing- and context-dependent manner. With timing shifts in the millisecond range, different types of synaptic plasticity are induced through different AChR subtypes with different mechanisms (pre- or post-synaptic). These results have thus revealed the striking temporal accuracy of modulatory transmitter systems and the subsequent complex functions achieved based on this capability.
This study also reveals novel physiologically reasonable neural activity patterns that induce synaptic plasticity, a very important question in learning and memory studies (Kandel, 2009
). The HFS-induced synaptic plasticity has provided valuable information in underlying molecular mechanisms, but has been questioned as a physiological firing pattern. For this reason, spike timing-dependent plasticity is considered physiologically more reasonable (Markram et al., 1997
; Kandel, 2009
). Even so, both models focus on manipulating the firing patterns of the same glutamatergic pathway where synaptic plasticity will form. In the present study, synaptic plasticity is induced by an extrinsic input and thus provides a mechanism to integrate information from extrinsic pathways and store it in local synapses. It is thus more relevant to understanding learning and memory, which always involves the precise coordination among multiple brain regions.
Cognitive deficits in AD have long been thought to be caused in part by cholinergic dysfunction (Bartus et al., 1982
; Terry and Buccafusco, 2003
). Here we have shown that concentrations of oligomeric Aβ as low as 10 nM largely blocks both forms of α7 nAChR-dependent plasticity. For the mAChR-mediated LTP, a concentration of Aβ of nearly 1 μM is required to block this form of plasticity; this concentration is comparable to those who previously have studied Aβ inhibition of hippocampal synaptic plasticity (Lambert et al., 1998; Vitolo et al., 2002
; Wang et al., 2004
). The synthetic Aβ is much less efficient than naturally secreted Aβ (about 1/200) in inhibiting hippocampal LTP (Wang et al., 2004
). The fact that the α7 nAChR-dependent plasticity is more sensitive to Aβ may be due to the previously reported ability of Aβ to bind to the α7 nAChR with high affinity. However the sensitivity of α7 nAChRs to Aβ may vary due to its coassembly with other subunits and/or among different neuronal populations (Liu et al., 2009
; Liu et al., 2001
; Pettit et al., 2001
), and Aβ may be exerting its effect on plasticity through other mechanisms (Nimmrich et al., 2008
). Nevertheless, these results thus provide a mechanism for Aβ to impair cholinergic-related synaptic plasticity and cognitive functions, and provides a relevant platform for further testing therapeutic compounds for cholinergic-dependent cognitive impairment including Alzheimer's disease.