# Lcn2 deficiency leads to long-lasting social impairments independent of maternal immune activation

## TL;DR

This study shows that Lcn2 deficiency and maternal immune activation both cause lasting social behavior issues in offspring, suggesting a shared mechanism in brain development.

## Contribution

The study reveals a novel role for Lcn2 in brain development and its intersection with maternal immune activation effects on social behavior.

## Key findings

- Lcn2 deficiency and maternal immune activation independently caused social deficits and repetitive behaviors in offspring.
- RNA sequencing showed overlapping gene expression changes in Lcn2 KO and maternal immune activation groups.
- The effects were specific to social and repetitive behaviors, with no impact on learning and memory.

## Abstract

Maternal infection during pregnancy is a well-established risk factor for neurodevelopmental disorders (NDDs), yet the underlying molecular mechanisms remain poorly understood. Lipocalin-2 (Lcn2), an innate immune protein, is highly upregulated during infection, known to affect neuronal and glial function. This study investigates the role of Lcn2 in shaping brain development, particularly after maternal immune activation (MIA). To mimic maternal infection, pregnant mice received intraperitoneal injections of either lipopolysaccharide (LPS) or saline on embryonic days 16 to 18 to model infection during the second trimester of pregnancy in humans. We first showed that Lcn2 mRNA was expressed in the fetal brain and that MIA significantly upregulated Lcn2 mRNA in the hippocampus and neocortex of both sexes. To assess functional relevance, we employed Lcn2 heterozygous females to generate wild-type and Lcn2 KO offspring from the MIA and control groups. Both female and male offspring underwent a battery of behavioral assays. Strikingly, both Lcn2 deletion and MIA independently led to social deficits and increased repetitive behaviors, hallmark features of NDDs, but their combination did not produce additive effects, suggesting a shared or converging mechanism. These alterations were specific to social and repetitive behavior, as no deficits were observed in the learning and memory task. To investigate potential shared molecular mechanisms, we quantified pro-inflammatory cytokine levels in the placenta and fetal forebrain at 4 h after the final LPS injection. No genotype-dependent differences were observed in IL-6, TNF-α, or IL-1β expression. However, RNA sequencing analysis revealed an overlapping group of differentially expressed genes in the Lcn2 KO and MIA groups, indicating convergence on similar transcriptional pathways that may underlie the observed behavioral phenotypes. Together, these findings reveal a previously unrecognized role for Lcn2 in brain development and suggest that while Lcn2 may not directly mediate the damaging effects of maternal immune challenge, it intersects with critical developmental pathways that shape social behavior.

The online version contains supplementary material available at 10.1186/s12974-026-03742-1.