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Fig. 1 | Molecular Neurodegeneration

Fig. 1

From: Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease

Fig. 1

Induction and expression of LTP in physiological and AD-related pathological conditions in animal models of AD-like pathology and its modulation by microbiota products. (A) In physiological conditions, optimal input to pre-synaptic hippocampal neurons triggers the release of glutamate into the synaptic cleft. This activates membrane AMPARs on the post-synaptic neurons and allows the entry of Na+ into the cell, yielding a excitatory postsynaptic potential (EPSP). When tetanic stimulation is given, a large amount of glutamate is released from presynaptic terminals, which increases the EPSP produced by postsynaptic membrane, resulting in the removal of Mg2+ blocked in NMDAR and its subsequent activation. NMDAR activation allows the influx of Ca2+ as well as Na+ ions into the cell, leading to the activation of Ca2+-calmodulin-dependent protein kinase-II, which phosphorylates AMPAR, increases its conductivity, promotes the transfer of AMPAR from the cytoplasm to the postsynaptic membrane and increases its density, resulting in LTP. (B) Early stages of AD-like pathology are likely associated with elevated glutamate release by pre-synaptic neurons and increased glutamate concentration in and around the synaptic cleft. Indeed, Aβ can stimulate glutamate release through α7nAchR activation on the pre-synaptic neuron and contribute to pre-synaptic facilitation. Pro-inflammatory cytokines, such as TNFα and IL-1β, produced by microglia in the presence of accumulating Aβ, can upregulate AMPAR expression on postsynaptic membrane, which allows higher ion influx and a greater depolarization. All of these changes at the synaptic level lead to a neuronal hyperactivation in the hippocampus and increased LTP in the early stages of AD. Microbiota metabolites such as SCFA, BA and TMAO have been identified in the brain (for details, see Impact of microbiota on neuroinflammation and AD and gut dysbiosis: link with neuroinflammation and involvement of microglia). The negative impact of TMAO on synaptic plasticity (i.e. LTP impairment) has been reported [76] but as the relevant experiments were carried on hippocampal slices ex-vivo which were incubated in the presence of TMAO, it is not clear presently whether TMAO exerts its effect directly on neurons, or indirectly by acting on microglia and subsequently affecting neuronal function via microglia-neuron cross-talk. In contrast, in the 5XFAD mouse model, sodium butyrate (one of the SCFAs) promoted synaptic plasticity as assessed by LTP electrophysiology recording in vivo [77]. The experimental set-up used in this study was unable to determine whether the observed impact on neuronal activity is direct or rather indirect (via microglia). There is currently no data on the putative impact of BA on neuronal activity. (C) Later stages of AD-like pathology are characterized by hypoactivity of the glutamatergic neurotransmission as a consequence of the paradox hyperactivity in earlier stages. Elevated Aβ levels yields reduced glutamate release by pre-synaptic neurons through inhibition of α7nAchRs, which reduces post-synaptic activation of NMDARs. Moreover, chronic stimulation of AMPARs during early stages of AD pathology leads to desensitization and internalization of these receptors. In addition, excessive production of pro-inflammatory cytokines (e. g. TNFα, IL-1β…) by microglia due to toxic conditions created by continued Aβ accumulation, can trigger neuronal death and release of glutamate from dying neurons, thus escalating neurotoxicity. Altogether, this results in reduced LTP and EPSP (and a mirror increase in LTD, not depicted in the figure for the sake of clarity) that are associated with cognitive deficits. Created with Biorender.com

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