Modestly increasing systemic interleukin-6 perinatally disturbs secondary germinal zone neurogenesis and gliogenesis and produces sociability deficits

TY - JOUR

T1 - Modestly increasing systemic interleukin-6 perinatally disturbs secondary germinal zone neurogenesis and gliogenesis and produces sociability deficits

AU - Velloso, Fernando Janczur

AU - Wadhwa, Anna

AU - Kumari, Ekta

AU - Carcea, Ioana

AU - Gunal, Ozlem

AU - Levison, Steven W.

N1 - Publisher Copyright: © 2021 Elsevier Inc.

PY - 2022/3

Y1 - 2022/3

N2 - Epidemiologic studies have demonstrated that infections during pregnancy increase the risk of offspring developing Schizophrenia, Autism, Depression and Bipolar Disorder and have implicated interleukin-6 (IL-6) as a causal agent. However, other cytokines have been associated with the developmental origins of psychiatric disorders; therefore, it remains to be established whether elevating IL-6 is sufficient to alter the trajectory of neural development. Furthermore, most rodent studies have manipulated the maternal immune system at mid-gestation, which affects the stem cells and progenitors in both the primary and secondary germinal matrices. Therefore, a question that remains to be addressed is whether elevating IL-6 when the secondary germinal matrices are most active will affect brain development. Here, we have increased IL-6 from postnatal days 3–6 when the secondary germinal matrices are rapidly expanding. Using Nestin-CreERT2 fate mapping we show that this transient increase in IL-6 decreased neurogenesis in the dentate gyrus of the dorsal hippocampus, reduced astrogliogenesis in the amygdala and decreased oligodendrogenesis in the body and splenium of the corpus callosum all by ∼ 50%. Moreover, the IL-6 treatment elicited behavioral changes classically associated with neurodevelopmental disorders. As adults, IL-6 injected male mice lost social preference in the social approach test, spent ∼ 30% less time socially engaging with sexually receptive females and produced ∼ 50% fewer ultrasonic vocalizations during mating. They also engaged ∼ 50% more time in self-grooming behavior and had an increase in inhibitory avoidance. Altogether, these data provide new insights into the biological mechanisms linking perinatal immune activation to complex neurodevelopmental brain disorders.

AB - Epidemiologic studies have demonstrated that infections during pregnancy increase the risk of offspring developing Schizophrenia, Autism, Depression and Bipolar Disorder and have implicated interleukin-6 (IL-6) as a causal agent. However, other cytokines have been associated with the developmental origins of psychiatric disorders; therefore, it remains to be established whether elevating IL-6 is sufficient to alter the trajectory of neural development. Furthermore, most rodent studies have manipulated the maternal immune system at mid-gestation, which affects the stem cells and progenitors in both the primary and secondary germinal matrices. Therefore, a question that remains to be addressed is whether elevating IL-6 when the secondary germinal matrices are most active will affect brain development. Here, we have increased IL-6 from postnatal days 3–6 when the secondary germinal matrices are rapidly expanding. Using Nestin-CreERT2 fate mapping we show that this transient increase in IL-6 decreased neurogenesis in the dentate gyrus of the dorsal hippocampus, reduced astrogliogenesis in the amygdala and decreased oligodendrogenesis in the body and splenium of the corpus callosum all by ∼ 50%. Moreover, the IL-6 treatment elicited behavioral changes classically associated with neurodevelopmental disorders. As adults, IL-6 injected male mice lost social preference in the social approach test, spent ∼ 30% less time socially engaging with sexually receptive females and produced ∼ 50% fewer ultrasonic vocalizations during mating. They also engaged ∼ 50% more time in self-grooming behavior and had an increase in inhibitory avoidance. Altogether, these data provide new insights into the biological mechanisms linking perinatal immune activation to complex neurodevelopmental brain disorders.

KW - Cell proliferation

KW - Cytokines

KW - Interleukin-6

KW - Stem cells

KW - Subgranular zone

KW - Subventricular zone

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UR - http://www.scopus.com/inward/citedby.url?scp=85121990331&partnerID=8YFLogxK

U2 - 10.1016/j.bbi.2021.12.015

DO - 10.1016/j.bbi.2021.12.015

M3 - Article

C2 - 34954074

SN - 0889-1591

VL - 101

SP - 23

EP - 36

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

ER -