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.

Keywords: PLX; behavior; dendritic spines; glutamatergic transmission; learning and memory; microglia; microglia depletion; synaptic plasticity.

FIGURE 1

(A) Temporal dynamics of microglia depletion and repopulation. Time-course of microglia depletion during administration of CSF1R inhibitors (PLX3397 and PLX5622) and repopulation upon treatment withdrawal, and time-course of genetic microglia depletion and repopulation induced by diphtheria toxin (DT) administration. Represented percentages of microglia in the brain have been extrapolated from published data (Elmore et al., 2014, 2018; Bruttger et al., 2015; Spangenberg et al., 2019; Basilico et al., 2021). (B) Advantages and disadvantages of microglia depletion methods. Summary of the main advantages and disadvantages of the different approaches used to deplete microglia (see section 2 for more detail).

FIGURE 2

Effects of microglial depletion on synaptic function and plasticity. Schematic representation of the reported effects of microglia depletion with CSF1R inhibitors (PLX3397 and PLX5622) and genetic DT-induced on dendritic spines, neurogenesis, perineuronal nets, excitatory and inhibitory (E/I) neurotransmission (see section 3 for more detail). DT: diphtheria toxin, HIPP: hippocampus, MC: motor cortex, OB: olfactory bulbs, PFC: prefrontal cortex, ST: striatum, VC: visual cortex. [1] Parkhurst et al., 2013; [2] Ma et al., 2020; [3] Reshef et al., 2014; [4] Wallace et al., 2020; [5] Rice et al., 2015; [6] Strackeljan et al., 2021; [7] Basilico et al., 2021; [8] Pinto et al., 2020; [9] Yegla et al., 2021; [10] De Luca et al., 2020; [11] Elmore et al., 2018; [12] Corsi et al., 2022; [13] Crapser et al., 2020; [14] Liu et al., 2021; [15] Badimon et al., 2020.

FIGURE 3

Effects of microglia depletion during adulthood on behavior in healthy rodents. Microglia depletion in the healthy adult brain does not have major effects on sensory perception¹, general locomotor activity, anxiety, sociability and working memory (blue). Motor function is impaired after genetic DT-induced microglia depletion (Parkhurst et al., 2014; Rubino et al., 2018), but not pharmacological depletion (yellow). Complex recognition memory and specific learning processes, such as “forgetting” and extinction of fear memories, are compromised in young mice with microglia depletion. Learning deficits are observed when microglia are depleted in juvenile or aged mice (red). Spatial learning is improved in young mice (green).¹An exception is reported by Rubino et al. (2018) that found altered gustatory perception in genetic DT-induced microglia depletion. ²Clodronate injection in the hippocampus have been reported to impair sociability and spatial learning in young mice (Torres et al., 2016). See section 4.1 and Supplementary Tables 1–8 for detailed information.

FIGURE 4

Impact of microglia depletion during development on adult behaviour. Graphic overview of studies that depleted microglia during specific developmental stages (from embryogenesis to adolescence) and assessed the behavioural performance later in time (during adolescence or adulthood). Briefly, microglia depletion during the embryonic and early postnatal periods causes longlasting behavioural and cognitive deficits (red), while transient postnatal microglia depletion had no subsequent impact on adult behaviour (blue). [1] Rosin et al., 2018; [2] Vanryzin et al., 2016; [3] Kana et al., 2019; [4] Soch et al., 2020; [5] Smith et al., 2020; [6] Ikezu et al., 2021. See section 4.2 for detailed information.