A cholinergic trigger drives learning-induced plasticity at hippocampal synapses

Abstract

Learning induces plastic changes in synapses. However, the regulatory molecules that orchestrate learning-induced synaptic changes are largely unknown. Although it is well established that cholinergic inputs from the medial septum modulate learning and memory, evidence for the cholinergic regulation of learning-induced synaptic plasticity is lacking. Here we find that the activation of muscarinic acetylcholine (ACh) receptors (mAChRs) mediates the contextual fear learning-driven strengthening of hippocampal excitatory pyramidal synapses through the synaptic incorporation of AMPA-type glutamate receptors (AMPARs). Contextual fear learning also enhances the strength of inhibitory synapses on hippocampal pyramidal CA1 neurons, in a manner mediated by the activation of, not mAChRs, but, nicotinic AChRs (nAChRs). We observe a significant correlation between the learning-induced increases in excitatory and inhibitory synaptic strength at individual pyramidal neurons. Understanding the mechanisms underlying cholinergic regulation of learning-induced hippocampal synaptic plasticity may help the development of new therapies for cognitive disorders.

Learning-Induced Synaptic Diversity and Quantification of Intra-Hippocampal Entropy

“…The ripple-like firing may code experienced information, as selective suppression of hippocampal ripples impairs spatial memory in dorsal CA1 [28]. Moreover, we previously found that contextual learning requires the plasticity at excitatory/inhibitory synapses in CA1 [8,9]. Our results, together with the previous studies, we hypothesized that the excitatory/inhibitory synaptic plasticity creates the ripple-like events to process the experienced context by using the theta phase-locked processing system.…”

“…A point with high appearance probability (around the mean level) indicates low self-entropy, while a point with very rare probability (a deviated point) indicates high self-entropy. Compared with untrained rats, the self-entropy per neuron was clearly increased in IA-trained rats but not in unpaired or walk-through rats [8]. This analysis suggests a learning-induced increase in the amount of information in CA1 neurons.…”

“…As to the inhibitory synaptic plasticity, nicotinic α7 receptor antagonist is known to block the strengthening of GABA A receptormediated synapses [8,11]. Since pharmacological blockade of the plasticity in bilateral CA1 impaired the learning, contextual learning seems to require the inhibitory synaptic plasticity in the CA1.…”

Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction

“…Moreover, several studies showed that hippocampal nAChR activation by nicotine and other nAChR agonists resulted in enhanced hippocampal LTP (Fujii and Sumikawa 2000;Welsby et al 2006Welsby et al , 2007Jia et al 2010); that is, strengthening of weak stimulation-induced short-term LTP (Fujii et al 1999;Matsuyama et al 2000;Matsuyama and Matsumoto 2003) as well as direct induction of LTP (He et al 2000;Matsuyama et al 2000;Matsuyama and Matsumoto 2003). Moreover, antagonism of nAChRs blocked learning-induced CA1 LTP (Mitsushima et al 2012). In addition to the effects of acute administration of nicotine and other direct nAChR agonists, hippocampal plasticity has been shown to be altered during nicotine withdrawal.…”

Anxiolytic effects of muscarinic acetylcholine receptors agonist oxotremorine in chronically stressed rats and related changes in BDNF and FGF2 levels in the hippocampus and prefrontal cortex

“…Moreover, mAChR activation can modulate the production or/and the release of neurotrophic factors in neurons, such as brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), which in turn could mediate synaptic plasticity, axon outgrowth, and neurogenesis (Barathi et al 2009;Lindholm et al 1994;Mudo et al 1996;Navakkode and Korte 2012). Several of these effects involve mainly M1 receptor in adult hippocampus (Dennis et al 2016;Mitsushima et al 2013).…”