Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus

Abstract

Parkinson's disease (PD) symptoms do not become apparent until most dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate, suggesting that compensatory mechanisms play a role. Here, we investigated the compensatory involvement of activated microglia in the SN pars reticulata (SNr) and the globus pallidus (GP) in a 6-hydroxydopamine-induced rat hemiparkinsonism model. Activated microglia accumulated more markedly in the SNr than in the SNc in the model. The cells had enlarged somata and expressed phagocytic markers CD68 and NG2 proteoglycan in a limited region of the SNr, where synapsin I- and postsynaptic density 95-immunoreactivities were reduced. The activated microglia engulfed pre- and post-synaptic elements, including NMDA receptors into their phagosomes. Cells in the SNr and GP engulfed red fluorescent DiI that was injected into the subthalamic nucleus (STN) as an anterograde tracer. Rat primary microglia increased their phagocytic activities in response to glutamate, with increased expression of mRNA encoding phagocytosis-related factors. The synthetic glucocorticoid dexamethasone overcame the stimulating effect of glutamate. Subcutaneous single administration of dexamethasone to the PD model rats suppressed microglial activation in the SNr, resulting in aggravated motor dysfunctions, while expression of mRNA encoding glutamatergic, but not GABAergic, synaptic elements increased. These findings suggest that microglia in the SNr and GP become activated and selectively eliminate glutamatergic synapses from the STN in response to increased glutamatergic activity. Thus, microglia may be involved in a negative feedback loop in the indirect pathway of the basal ganglia to compensate for the loss of dopaminergic neurons in PD brains.

Phagocytic elimination of synapses by microglia during sleep

“…Therefore, we investigated the effects of NA on primary cultured microglial cells. As has been described previously (Aono et al, ), glutamate (Glu; 5 μM) enhanced phagocytic internalization of red fluorescent particles of PKH26 (Figure a). When simultaneously incubated with Glu (5 μM) and NA (10 μM) for 2 hr, the Glu‐mediated enhancement of phagocytosis was abolished.…”

“…Circadian changes in LC‐derived NA contents in the brain (Aston‐Jones & Bloom, ) and the suppressive effects of NA on microglia are well‐known (Ishii et al, ; Mori et al, ). Glu enhances phagocytic activity of primary cultured rat microglia (Aono et al, ), and NA overcomes the Glu‐induced enhancement, as was shown in the present study. Decline of NA contents caused by senescent degeneration of the LC has been implicated in pathologic activation of microglia in Alzheimer's disease (Heneka et al, ).…”

“…Glu enhances phagocytic activity of primary cultured rat microglia (Aono et al, 2017), and NA overcomes the Glu-induced enhancement, as was shown in the present study. Decline of NA contents caused by senescent degeneration of the LC has been implicated in pathologic activation of microglia in Alzheimer's disease (Heneka et al, 2010).…”

“…Dex increased mRNA encoding synapsin I, but decreased mRNA for MMP2, C1qb, MFG‐E8, CX3CR1, and CD68 (Figure c). Synapsin I mRNA is abundantly present in the synaptosomal fraction (Aono et al, ). The Dex‐induced changes at ZT0 in synaptic and microglial proteins resembled changes in the control brain at ZT12, as shown in Figure .…”

Favorable and unfavorable roles of microglia and macrophages in the pathologic central nervous system

“…The microglia-derived proinflammatory cytokines and chemokines may also contribute to aggravation. Injection of 6-hydorxydopamine (6-OHDA) into the striatum or medial forebrain bundle is used to prepare the PD rat model [47,48] . In the model, DA neurons in the SNc primarily undergo degeneration, and microglia then become activated in response to damage-associated molecular patterns (DAMPs), such as high mobility group box-1 protein (HMGB1) released from damaged neurons [49] .…”