What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior

Abstract

Microglia are dynamic cells, constantly surveying their surroundings and interacting with neurons and synapses. Indeed, a wealth of knowledge has revealed a critical role of microglia in modulating synaptic transmission and plasticity in the developing brain. In the past decade, novel pharmacological and genetic strategies have allowed the acute removal of microglia, opening the possibility to explore and understand the role of microglia also in the adult brain. In this review, we summarized and discussed the contribution of microglia depletion strategies to the current understanding of the role of microglia on synaptic function, learning and memory, and behavior both in physiological and pathological conditions. We first described the available microglia depletion methods highlighting their main strengths and weaknesses. We then reviewed the impact of microglia depletion on structural and functional synaptic plasticity. Next, we focused our analysis on the effects of microglia depletion on behavior, including general locomotor activity, sensory perception, motor function, sociability, learning and memory both in healthy animals and animal models of disease. Finally, we integrated the findings from the reviewed studies and discussed the emerging roles of microglia on the maintenance of synaptic function, learning, memory strength and forgetfulness, and the implications of microglia depletion in models of brain disease.

Cx3cr1 deficiency interferes with learning‐ and direct current stimulation‐mediated neuroplasticity of the motor cortex

“…In contrast, other studies reported an increase in hippocampal LTP in full knockouts (Maggi et al, 2011; Milior et al, 2016). Importantly, in addition to methodological differences, the region‐specific role of microglial phenotypes and properties, including CX3CR1‐signalling, has previously been discussed as a reason for these discrepancies, which have also to be considered in comparison with our motor cortical data (Basilico et al, 2022). Another molecular mechanisms underlying our results could be inferred from our previous finding that brain‐derived neurotrophic factor (BDNF) release plays a key role in the neuroplastic effects of DCS (Fritsch et al, 2010; A. K. Gellner et al, 2019) and from others showing that microglia‐derived BDNF is essential for motor cortical plasticity (Parkhurst et al, 2013).…”

“…These regions might be additionally relevant for the phenotypes we and others observed. Moreover, regional differences regarding microglia properties and their impact on neuroplasticity, even between different cortical areas, have been reported (Basilico et al, 2022; Tan et al, 2020). Consequently, our data exclusively from the motor cortex have to be carefully interpreted in comparison to studies from other brain regions.…”

Zymosan A produces a rapid and sustained antidepressant effect in chronically stressed mice by stimulating hippocampal microglia

“…How then does microglial activation mediate the rapid antidepressant effect of zymosan A? In the resting state, microglia are mainly responsible for maintaining brain homeostasis by clearing neuronal debris (Cowan and Petri, 2018) and altering synaptic plasticity (Basilico et al ., 2022). We hypothesize that zymosan A first activates microglia in the hippocampus, thereby promoting excitatory neurotransmission and producing antidepressant effects.…”

B cells and the stressed brain: emerging evidence of neuroimmune interactions in the context of psychosocial stress and major depression

“…Moreover, various BAFF B cell survival signal inhibitors (e.g., Belimumab) are being developed or are currently deployed in clinical populations. Treatments developed for other therapeutic applications that are directed against other central [e.g., microglial depletion with colony stimulating factor 1 receptor inhibitors (PLX3397) ( Basilico et al, 2022 )] or systemic [e.g., anti-CD3 muromonab ( Kuhn and Weiner, 2016 )] immune cell populations can be used for discerning the extent to which interactions with other cells types is an important mechanism by which B cells influence the response to stress. MAbs directed against distinct cytokines are also available.…”