Microglial Tmem59 Deficiency Impairs Phagocytosis of Synapse and Leads to Autism-Like Behaviors in Mice

Abstract

Synaptic abnormality is an important pathologic feature of autism spectrum disorders (ASDs) and responsible for various behavioral defects in these neurodevelopmental disorders. Microglia are the major immune cells in the brain and also play an important role in synapse refinement. Although dysregulated synaptic pruning by microglia during the brain development has been associated with ASDs, the underlying mechanism has yet to be fully elucidated. Herein, we observed that expression of Transmembrane protein 59 (TMEM59), a protein recently shown to regulate microglial function, was decreased in autistic patients. Furthermore, we found that both male and female mice with either complete or microglia-specific loss of Tmem59 developed ASD-like behaviors. Microglial TMEM59-deficient mice also exhibited enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated levels of excitatory synaptic proteins in synaptosomes. TMEM59-deficient microglia had impaired capacity for synapse engulfment both in vivo and in vitro. Moreover, we demonstrated that TMEM59 interacted with the C1q receptor CD93 and TMEM59 deficiency promoted CD93 protein degradation in microglia. Downregulation of CD93 in microglia also impaired synapse engulfment. These findings identify a crucial role of TMEM59 in modulating microglial function on synapse refinement during brain development and suggest that TMEM59 deficiency may contribute to ASDs through disrupting phagocytosis of excitatory synapse and thus distorting the excitatory-inhibitory (E/I) neuronal activity balance.

Bergaptol Alleviates LPS-Induced Neuroinflammation, Neurological Damage and Cognitive Impairment via Regulating the JAK2/STAT3/p65 Pathway

“… 21 , 22 On the other hand, microglia also play a key role in synaptic refinement, and abnormal microglia show dysfunctional synaptic pruning ability, which is an important cause of neural dysfunction. 23 In our study, Bergaptol treatment significantly improved cognitive impairment in LPS-treated mice. Further analysis of changes in hippocampal neuron morphology in mice revealed that Bergaptol treatment significantly reduced the level of nucleus fixation in hippocampal neurons of LPS-treated mice and alleviated the reduction in hippocampal neuron spine density.…”

Microglia and astrocytes underlie neuroinflammation and synaptic susceptibility in autism spectrum disorder

“…A mouse model lacking CX3CR1 showed a transient decrease in microglia and a consequent defect in synaptic pruning during the early postnatal period. In a mouse model of microglial Tmem59 deletion, deletion of microglial Tmem59 impaired synaptic phagocytosis, leading to autism-like behavior ( Meng et al, 2022 ). In autism models, a transient decrease in microglia is followed by a synaptic pruning defect, strongly associated with autistic behaviors such as social deficits.…”

Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities

“…Previous studies have revealed that the disruption of E/I balance contributes to the pathogenesis of autism spectrum disorders (ASD). 16 , 17 , 18 , 19 , 20 We, therefore, investigated if an alteration of autistic‐like behaviors occurred in the β3 E182G KI mice by evaluating their performances in social interaction and locomotor activity. In a three‐chambered social interaction test with a mouse (M) versus a toy (T), we found that the KI mice displayed obvious social deficits as reflected by a significant reduction in both number (WT: 1.24 ± 0.12, n = 16; KI: 0.92 ± 0.07, n = 13; p = 0.026; Figure 5A,B ) and time (WT: 1.33 ± 0.24, n = 16; KI: 0.67 ± 0.12, n = 13; p = 0.024; Figure 5A,C ) of the social index (SI), compared to WT controls.…”

“… 7 The β3 subunit is more broadly expressed than the β2 subunit in the mammalian brain, including cerebral cortex, hippocampus and hypothalamus, 12 , 13 and serves as one of the most important subunits regulating GABA A R function at both circuit 14 and behavioral levels. 1 , 2 , 15 , 16 Therefore, we hypothesized that mice harboring glutamate‐binding deficient GABA A Rs generated by KI of β3 Glutamic acid 182 to Glycine (E182G) mutation would have significantly diminished glutamate potentiation on most native GABA A Rs, thereby exhibiting overexcitation phenotypes.…”