Complement-dependent loss of inhibitory synapses on pyramidal neurons followingToxoplasma gondiiinfection

Abstract

AbstractThe apicomplexan parasiteToxoplasma gondiihas developed mechanisms to establish a central nervous system infection in virtually all warm-blooded animals. AcuteT. gondiiinfection can cause neuroinflammation, encephalitis, and seizures. Meanwhile, studies in humans, non-human primates, and rodents have linked chronicT. gondiiinfection with altered behavior and increased risk for neuropsychiatric disorders, including schizophrenia. We previously demonstrated thatT. gondiiinfection triggers the loss of perisomatic inhibitory synapses, an important source of inhibition on excitatory pyramidal cells, and a type of synapse that is disrupted in neurological and neuropsychiatric disorders. Similar to other instances of inflammation and neurodegeneration, we showed that phagocytic cells (including microglia and infiltrating monocytes) contribute to the loss of these inhibitory synapses. However, in the case ofT. gondii-induced synapse loss, phagocytic cells target and ensheath the cell bodies of telencephalic neurons. Here, we show that these phagocytic cells specifically ensheath excitatory pyramidal neurons, leading to the preferential loss of perisomatic synapses on these neurons. In contrast, inhibitory cortical interneuron subtypes are not extensively ensheathed by phagocytic cells following infection. Moreover, we show that infection induces expression of complement C3 protein by these excitatory neurons and that C3 is required for the loss of perisomatic inhibitory synapses, albeit not through activation of the classical complement pathway. Together, these findings provide evidence thatT. gondiiinfection induces changes in excitatory pyramidal neurons that trigger selective removal of inhibitory perisomatic synapses in the infected neocortex and provide a novel role for complement in remodeling of inhibitory circuits in the infected brain.