Inhibition of NKCC1 Ameliorates Anxiety and Autistic Behaviors Induced by Maternal Immune Activation in Mice

Abstract

Autism spectrum disorder (ASD) is thought to result from susceptibility genotypes and environmental risk factors. The offspring of women who experience pregnancy infection have an increased risk for autism. Maternal immune activation (MIA) in pregnant animals produces offspring with autistic behaviors, making MIA a useful model for autism. However, how MIA causes autistic behaviors in offspring is not fully understood. Here, we show that NKCC1 is critical for mediating autistic behaviors in MIA offspring. We confirmed that MIA induced by poly(I:C) infection during pregnancy leads to autistic behaviors in offspring. We further demonstrated that MIA offspring showed significant microglia activation, excessive dendritic spines, and narrow postsynaptic density (PSD) in their prefrontal cortex (PFC). Then, we discovered that these abnormalities may be caused by overexpression of NKCC1 in MIA offspring’s PFCs. Finally, we ameliorated the autistic behaviors using PFC microinjection of NKCC1 inhibitor bumetanide (BTN) in MIA offspring. Our findings may shed new light on the pathological mechanisms for autism caused by pregnancy infection.

Animal Models of Autistic-Like Behavior: Is the Time for a Scoring System with More Accurate Definitions?

“…Several rodent models of ASD-like behavior have been developed, to recapitulate human disease phenotype, by eliciting infectious processes prenatally or early postnatally using varieties of biological maneuvers [15,16]. Most frequently, polyinosinic-polycytidylic acid (PolyIC), a double-stranded RNA molecule that stimulates an immune response through the activation of toll-like receptor 3 is widely employed to model autism in rodents [17][18][19]. Lipopolysaccharide (LPS) and propionic acid are also well-documented immunogens used pre-and postnatally to induce autism in rodent models [20][21][22][23].…”