Microglia control glutamatergic synapses in the adult mouse hippocampus

Abstract

Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3‐CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX‐induced synaptic changes were absent in Cx3cr1−/− mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses.

Microglia maintain the normal structure and function of the hippocampal astrocyte network

“…However, there are also discrepancies in the results between ours and others. For example, microglia ablation in our hands did not induce noticeable astrogliosis, but an enhanced GFAP expression was observed by Basilico et al (2022). An increase or decrease in PPR ratio was reported after microglia depletion by others (Basilico et al, 2022; Corsi et al, 2022).…”

“…Similar to our data showing that microglia depletion does not affect the PPR (Figure 5), priming microglia with LPSx4 did not affect the PPR (PBS = 1.89 ± 0.03 [ n = 23] vs. LPSx4 = 1.93 ± 0.04 [ n = 25], p = .453) (Figure 7a,b). When these normal PPRs are considered together with data showing that axonal integrity is unaffected by priming microglia (based on normal fiber volley amplitudes; see Figure 7b), we can conclude that microglia regulate synaptic transmission at least in part via post‐synaptic mechanisms (Figure 6b), although presynaptic mechanisms have also been reported (Basilico et al, 2022; Clark et al, 2015).…”

“…Most studies using PLX5622 have been performed in the adult mouse (>P56) (Elmore et al, 2014; Freria et al, 2020; Spangenberg et al, 2019; Willis et al, 2020), which eat more chow per day than younger mice (Ellacott et al, 2010). However, recently published data indicate that similar depletion efficacy can be achieved in younger mice (Basilico et al, 2022). Here, we independently confirm that effective microglia depletion can be achieved in P25‐P45 mouse brains (Figure S1a,b).…”

“…LTP is a persistent strengthening of synaptic activity that produces a long‐lasting increase in signal transmission between two neurons. Since others have shown microglia presence can either decrease (Basilico et al, 2022; Corsi et al, 2022; Yegla et al, 2021), or increase (Zhou et al, 2011) neurotransmission (see also, Discussion), we sought to understand the relationship between microglia depletion, astrocyte network disruption, and LTP. We observed that the magnitude of LTP was not different between groups (Vehicle = 175 ± 15.6% vs. PLX5622 = 186 ± 16.0%; n = 6/group, p = .649; Figure 5c,d), indicating that the induction of LTP does not require microglia.…”

“…Microglia regulate activity‐dependent plasticity and synaptic remodeling of neuronal networks in the brain during development and in adults in both health and disease. Specifically, in response to neuronal cues (e.g., fractalkine and ATP), microglia monitor the health and function of neurons and regulate synaptic strength and connectivity of neural networks (Badimon et al, 2020; Basilico et al, 2022; Cserep et al, 2020; Eyo et al, 2014; Liu et al, 2021; Wu et al, 2020). These microglia–neuron interactions have been extensively studied in hippocampus, although functionally important microglia‐dependent effects have also been documented in spinal cord, motor cortex and visual cortex (Chen et al, 2014; Clark et al, 2015; Liu et al, 2021; Zhou et al, 2019).…”