2. Academic Validation
  3. Effects of pharmacological inhibition of FABP4 during gestation and lactation on offspring neurodevelopment and behavior

Effects of pharmacological inhibition of FABP4 during gestation and lactation on offspring neurodevelopment and behavior

  • Neurosci Lett. 2025 Mar 14:853:138199. doi: 10.1016/j.neulet.2025.138199.
Sun Zhengkang 1,  Hinako Kirikae 1,  He Xiaofeng 1,  Fumiko Yoshimachi 1,  Minori Ikuta 1,  Tetsuo Ohnishi 2,  Yui Yamamoto 1,  Hirofumi Miyazaki 1,  Yoshiyuki Kasahara 3,  Mai Sakai 4,  Zhiqian Yu 5,  Noriko Osumi 6,  Hiroaki Tomita 7,  Yuji Owada 8,  Motoko Maekawa 9
Affiliations

Affiliations

  • 1 Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan.
  • 2 Department of Nutrition, Akita Nutrition Junior College, Akita, Japan.
  • 3 Department of Maternal and Fetal Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan.
  • 4 Department of Disaster Psychiatry, International Research Institute for Disaster Science, Tohoku University, Sendai, Japan.
  • 5 Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
  • 6 Department of Developmental Neuroscience, Graduate School of Medicine, Tohoku University, Sendai, Japan.
  • 7 Department of Disaster Psychiatry, International Research Institute for Disaster Science, Tohoku University, Sendai, Japan; Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
  • 8 Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: yuji.owada.e2@tohoku.ac.jp.
  • 9 Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: motoko.maekawa.c7@tohoku.ac.jp.
PMID: 40090510 DOI: 10.1016/j.neulet.2025.138199
Abstract

Fatty acid-binding protein 4 (FABP4), a key regulator of lipid metabolism and inflammation, has been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). This study investigated the effects of FABP4 inhibition during gestation and lactation on offspring neurodevelopment using the selective FABP4 inhibitor BMS309403. Female mice received BMS309403 (15 mg/kg) via oral gavage from two weeks before mating to postnatal day 28 (P28). Administration of BMS309403 to mouse dams resulted in autism-like phenotypes in male offspring (behavioral tests: n = 7-10 per group; spine analysis: 6 mice per group, n = 26-38 dendrites per group), characterized by increased dendritic spine density in the prefrontal cortex, impaired vocal communication, increased repetitive behaviors, and depression-like symptoms. Fatty acid analysis (n = 4-6 per group) revealed significant alterations in maternal and fetal lipid profiles, including elevated arachidonic acid levels in maternal plasma and increased n6PUFAs in the fetal brain, suggesting a pro-inflammatory lipid environment. Principal component analysis demonstrated distinct clustering of lipid profiles between control and BMS309403-treated groups. Cytokine analysis (n = 6 per group) indicated reductions in IL-10 and IL-12(p40) in maternal plasma and decreased TNFα in the fetal plasma, suggesting dysregulation in systemic inflammatory signaling. These findings suggest that FABP4 inhibition during the perinatal period perturbs lipid metabolism and may influence neurodevelopment through systemic metabolic changes. Although the direct effects of BMS309403 on the fetal brain cannot be excluded, alteration in maternal metabolism and placental function may have contributed to the observed neurodevelopmental changes in offspring.

Keywords

Autism spectrum disorder; Brain development; Fatty acid binding protein 4; Lipid metabolism.

Figures
Products