Immune synaptopathies: how maternal immune activation impacts synaptic function during development

Abstract

In the last two decades, the term synaptopathy has been largely used to underline the concept that impairments of synaptic structure and function are the major determinant of brain disorders, including neurodevelopmental disorders. This notion emerged from the progress made in understanding the genetic architecture of neurodevelopmental disorders, which highlighted the convergence of genetic risk factors onto molecular pathways specifically localized at the synapse. However, the multifactorial origin of these disorders also indicated the key contribution of environmental factors. It is well recognized that inflammation is a risk factor for neurodevelopmental disorders, and several immune molecules critically contribute to synaptic dysfunction. In the present review, we highlight this concept, which we define by the term "immune-synaptopathy," and we discuss recent evidence suggesting a bi-directional link between the genetic architecture of individuals and maternal activation of the immune system in modulating brain developmental trajectories in health and disease.

Keywords: brain-immune system cross-talk; maternal immune activation; neurodevelopmental diseases; prenatal inflammation; synapse.

Figure 1. Prenatal immune activation results in altered spine density in the offspring brain

The type and extent of the effects depend on dosage and timing of the immune stimulus and analyzed brain area.

Figure 2. Cytokines affecting neuronal pathways fundamental for synaptic structure and function

Figure 3. The activation of the immune system can directly affect molecular components previously identified as involved in synaptopathies

A–D. See text for details.