Immune-Triggered Forms of Plasticity Across Brain Regions

Abstract

Immune cells play numerous roles in the host defense against the invasion of microorganisms and pathogens, which induces the release of inflammatory mediators (e.g., cytokines and chemokines). In the CNS, microglia is the major resident immune cell. Recent efforts have revealed the diversity of the cell types and the heterogeneity of their functions. The refinement of the synapse structure was a hallmark feature of the microglia, while they are also involved in the myelination and capillary dynamics. Another promising feature is the modulation of the synaptic transmission as synaptic plasticity and the intrinsic excitability of neurons as non-synaptic plasticity. Those modulations of physiological properties of neurons are considered induced by both transient and chronic exposures to inflammatory mediators, which cause behavioral disorders seen in mental illness. It is plausible for astrocytes and pericytes other than microglia and macrophage to induce the immune-triggered plasticity of neurons. However, current understanding has yet achieved to unveil what inflammatory mediators from what immune cells or glia induce a form of plasticity modulating pre-, post-synaptic functions and intrinsic excitability of neurons. It is still unclear what ion channels and intracellular signaling of what types of neurons in which brain regions of the CNS are involved. In this review, we introduce the ubiquitous modulation of the synaptic efficacy and the intrinsic excitability across the brain by immune cells and related inflammatory cytokines with the mechanism for induction. Specifically, we compare neuro-modulation mechanisms by microglia of the intrinsic excitability of cerebellar Purkinje neurons with cerebral pyramidal neurons, stressing the inverted directionality of the plasticity. We also discuss the suppression and augmentation of the extent of plasticity by inflammatory mediators, as the meta-plasticity by immunity. Lastly, we sum up forms of immune-triggered plasticity in the different brain regions with disease relevance. Together, brain immunity influences our cognition, sense, memory, and behavior via immune-triggered plasticity.

Investigating microglia-neuron crosstalk by characterizing microglial contamination in human and mouse Patch-seq datasets

“…A second alternative hypothesis is that microglial processes might be chemotaxing near neurons that have been otherwise altered or damaged, for example by the slice preparation procedure, but such neuron-microglia interactions might not be directly causing alterations to cellular electrophysiology. Because of the observational nature of our study, we cannot directly reconcile these competing explanations as doing so would likely require further experiments that directly perturb microglia; nevertheless, our findings are consistent with a growing body of work indicating that microglia directly regulate aspects of neuron excitability (Badimon et al, 2020; Cserép et al, 2020; Hikosaka et al, 2022).…”

“…Lastly, we next wanted to assess whether microglial contamination in Patch-seq might be associated with altered excitability of the recorded neuron. We were especially motivated to study this following our observations that microglia contamination is associated with the upregulation of specific transcripts known to causally mediate downstream changes in neuronal excitability (Hikosaka et al, 2022). Because each Patch-seq sampled neuron was first characterized for its intrinsic electrophysiological characteristics prior to mRNA harvesting, we were able to leverage this data to ask how microglial contamination might be associated with cell-to-cell variability in electrophysiological features across neuron subtypes and species.…”

“…Numerous genes were overexpressed in Patch-seq neurons with high contamination (Figure 3A, C, human: Supplementary Table 1, mouse: Supplementary Table 2), with 567 genes in human samples and 422 genes in mouse samples (log2 fold-change >2.5; p-value < 0.01). Crucially, this analysis revealed a number of genes that were upregulated in Patch-seq samples with high microglial contamination that are further known to mediate microglial cells' role in regulating aspects of neuronal excitability, including TNF, IL1B, IL6, and CCL2 (Hikosaka et al, 2022); these example genes are particularly salient as they were not also used to define the microglia contamination score (see Methods).…”

“…Microglia actively survey neural circuit excitability and can undertake a role similar to inhibitory cells to maintain the synchrony and homeostasis of local neuron activity (Badimon et al, 2020). Microglia achieve this by forming direct contacts with neuronal cell bodies (Akiyoshi et al, 2018; Cserép et al, 2020) or by secreting specific molecules such as ATP, TNF-α, IL1B, and other cytokines (Hikosaka et al, 2022). However, the effects of this regulation are highly varied among different neuronal types and brain regions.…”

Unmasking the dynamics of Mycoplasma gallisepticum: deciphering HD11 macrophage polarization for innovative infection control strategies

“…However, the precise mechanisms by which MG attacks HD11 cells remain unclear. Macrophage defense against pathogen invasion is an important component of host innate immunity ( Hikosaka et al, 2022 ). Currently, it is not clear in what way MG attacks HD11 cells.…”