Microglial diversity along the hippocampal longitudinal axis impacts synaptic plasticity in adult male mice under homeostatic conditions

Abstract

The hippocampus is a plastic brain area that shows functional segregation along its longitudinal axis, reflected by a higher level of long-term potentiation (LTP) in the CA1 region of the dorsal hippocampus (DH) compared to the ventral hippocampus (VH), but the mechanisms underlying this difference remain elusive. Numerous studies have highlighted the importance of microglia–neuronal communication in modulating synaptic transmission and hippocampal plasticity, although its role in physiological contexts is still largely unknown. We characterized in depth the features of microglia in the two hippocampal poles and investigated their contribution to CA1 plasticity under physiological conditions. We unveiled the influence of microglia in differentially modulating the amplitude of LTP in the DH and VH, showing that minocycline or PLX5622 treatment reduced LTP amplitude in the DH, while increasing it in the VH. This was recapitulated in Cx3cr1 knockout mice, indicating that microglia have a key role in setting the conditions for plasticity processes in a region-specific manner, and that the CX3CL1–CX3CR1 pathway is a key element in determining the basal level of CA1 LTP in the two regions. The observed LTP differences at the two poles were associated with transcriptional changes in the expression of genes encoding for Il-1, Tnf-α, Il-6, and Bdnf, essential players of neuronal plasticity. Furthermore, microglia in the CA1 SR region showed an increase in soma and a more extensive arborization, an increased prevalence of immature lysosomes accompanied by an elevation in mRNA expression of phagocytic markers Mertk and Cd68 and a surge in the expression of microglial outward K+ currents in the VH compared to DH, suggesting a distinct basal phenotypic state of microglia across the two hippocampal poles. Overall, we characterized the molecular, morphological, ultrastructural, and functional profile of microglia at the two poles, suggesting that modifications in hippocampal subregions related to different microglial statuses can contribute to dissect the phenotypical aspects of many diseases in which microglia are known to be involved.

Denervated mouse CA1 pyramidal neurons express homeostatic synaptic plasticity following entorhinal cortex lesion

“…However, it is not yet clear which factors are responsible for the diversity of homeostatic adjustments ( Lee et al, 2014 ). While synaptic architecture of specific pathways could account for these observations ( O'Rourke et al, 2012 ; Sancho et al, 2021 ), recent evidence suggests that glial cells may also be involved in this process, e.g., through differences in their local specializations or by modulating the myelination of axons ( Sipe et al, 2016 ; Jang et al, 2019 ; Bonetto et al, 2021 ; De Felice et al, 2022 ). Additionally, we hypothesize that the predominance of synaptic plasticity in certain pathways may result from the complexity and specialization of neural circuits ( Johnson et al, 1996 ; Dubovyk and Manahan-Vaughan, 2018 ; Sun et al, 2021 ).…”

Microglia regulate motor neuron plasticity via reciprocal fractalkine/adenosine signaling

“…Fractalkine/CX3CR1 signaling is an important regulator of hippocampal synaptic plasticity 2,3,74,75 . Differential microglial expression of pro-inflammatory cytokines (IL6, TNFα, IL1β), as well as BDNF in ventral vs dorsal hippocampus, is associated with reduced dorsal and increased ventral LTP 74 , suggesting complexity similar to our findings with spinal, phrenic motor plasticity. With impaired CX3CR1 signaling, hippocampal LTP can be restored by IL1β receptor antagonists 76 .…”

“…Fractalkine/CX3CR1 signaling is an important regulator of hippocampal synaptic plasticity 2,3,74,75 .…”

Phenomic Microglia Diversity as a Druggable Target in the Hippocampus in Neurodegenerative Diseases

“…Consequently, microglia may exist in n possible phenomic states, diverse in health and disease conditions, and which depend not only on the type and intensity of insult and on the progression of the disease, but also on the brain structure where microglia are located [37,[40][41][42][43][44]. The vast array of receptors expressed by microglia constantly surveying their surroundings constitutes a 'sensome', allowing detection and response to different stimuli that derive from sensory and behavioral experiences [1,45,46]. on the brain structure where microglia are located [37,[40][41][42][43][44].…”

“…on the brain structure where microglia are located [37,[40][41][42][43][44]. The vast array of receptors expressed by microglia constantly surveying their surroundings constitutes a 'sensome', allowing detection and response to different stimuli that derive from sensory and behavioral experiences [1,45,46]. [47]).…”