Abstract
Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL/6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.
Highlights
Alterations in cognitive function and behavior are often observed in the context of systemic inflammation and/or infection of the central nervous system [1,2,3]
Tissue cultures were treated with 1 μg/ml of LPS or vehicle-only for three days before the experimental assessment, and AMPA receptor-mediated miniature excitatory postsynaptic currents were recorded from individual CA1 pyramidal neurons in whole-cell configuration after the treatment period (Figures 1C, D)
Consistent with our previous work [19, 21], increased miniature excitatory postsynaptic currents (mEPSCs) amplitudes were observed 2–4 h following 10 Hz repetitive magnetic stimulation (rMS) in vehicle-only tissue cultures
Summary
Alterations in cognitive function and behavior are often observed in the context of systemic inflammation and/or infection of the central nervous system [1,2,3]. Several immune mediators that affect the ability of neurons to express plasticity have been identified [4, 5]. This is of considerable relevance in the context of neurological and psychiatric diseases associated with increased levels of pro-inflammatory cytokines in the brain [6,7,8,9]. Diagnostic approaches to functionally assess and quantify inflammation-associated alterations in neuronal plasticity and to monitor the effects of (plasticity-restoring) therapeutic interventions as yet remain underdeveloped. Consecutive trains of TMS pulses (repetitive TMS, rTMS) over the motor cortex promote enduring changes of cortical excitability, i.e., neural plasticity [12]. Since rTMS induces plasticity phenomena, in the present study, we hypothesize that this form of plasticity will be affected by neural inflammation
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