Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning

Abstract

Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.

Microglia roles in synaptic plasticity and myelination in homeostatic conditions and neurodevelopmental disorders

“…Such remodeling of neuronal synapses occurs constantly throughout life (Wu et al, 2015), with synaptic connections in many areas constantly undergoing remodeling based on experience, resulting in synaptic plasticity (Tremblay et al, 2010). Connectivity-refinement deficits may lead to the impairment of brain wiring as implicated in the etiology of several neurodevelopmental disorders (Sekar et al, 2016;Thion, Ginhoux, & Garel, 2018;Zhan et al, 2014), including ASD (Filipello et al, 2018) (Sellgren et al, 2019). Excessive synaptic pruning was shown to occur in this subject-derived cellular model (Sellgren et al, 2019).…”

“…Connectivity‐refinement deficits may lead to the impairment of brain wiring as implicated in the etiology of several neurodevelopmental disorders (Sekar et al, ; Thion, Ginhoux, & Garel, ; Zhan et al, ), including ASD (Filipello et al, ) and schizophrenia (McGlashan & Hoffman, ) (Figure ). A recent study utilized microglia‐like cells through cellular reprogramming of monocytes from schizophrenia subjects (Sellgren et al, ). Excessive synaptic pruning was shown to occur in this subject‐derived cellular model (Sellgren et al, ).…”

“…A recent study utilized microglia‐like cells through cellular reprogramming of monocytes from schizophrenia subjects (Sellgren et al, ). Excessive synaptic pruning was shown to occur in this subject‐derived cellular model (Sellgren et al, ). Moreover, synaptic elimination affects age‐associated cognitive decline and the development of several neurodegenerative disorders (Kim & Joh, ).…”

“…Following their establishment in the CNS, microglia are highly mobile and primarily use an amoeboid morphology to regulate neural circuits (Nayak, Roth, & McGavern, 2014) F I G U R E 3 Alteration of microglial properties and molecular signaling in neurodevelopmental disorders. Microglial alterations, such as morphological abnormalities, altered microglial density and cell number (Morgan et al, 2010), high levels of inflammatory cytokines (Vargas, Nascimbene, Krishnan, Zimmerman, & Pardo, 2005) and glutamate (Maezawa & Jin, 2010), compromised phagocytosis (Sekar et al, 2016), excess synapses, and altered connectivity (Filipello et al, 2018;Sellgren et al, 2019), have been shown to occur in neurodevelopmental disorders. Moreover, molecular alterations, such as upregulation of SHANK proteins and Psd95 in neurons (Kim et al, 2017), altered TREM2 expression (Edmonson, Ziats, & Rennert, 2014;Filipello et al, 2018), and elevated levels of CX3CR1 and BDNF in microglia have been associated with ASD (Edmonson et al, 2014;Ricci et al, 2013).…”

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

“…Mice lacking copies of C4 showed fewer synaptic inputs in a visual circuit that normally undergoes synaptic pruning, experimentally validating the functional impact of these associations. Adding further causal evidence, a recent study replicated this pruning effect in human cells using patient‐derived human neural cultures, and even showed that this mechanism of pathology can be targeted therapeutically . These studies explain a small yet important part of the causal pathophysiology, including cell types and biological processes, that lead to risk for schizophrenia, and are particularly exciting as until this point there had been no causal pathophysiology identified for this complex disorder.…”