Environmental exposure to common pesticide induces synaptic deficit and social memory impairment driven by neurodevelopmental vulnerability of hippocampal parvalbumin interneurons

Jessica Di Re; Leandra Koff; Yosef Avchalumov; Aditya K Singh; Timothy J Baumgartner; Mate Marosi; Lisa M Matz; Lance M Hallberg; Bill T Ameredes; Erin H Seeley; Shelly A Buffington; Thomas A Green; Fernanda Laezza

doi:10.1016/j.jhazmat.2024.136893

Environmental exposure to common pesticide induces synaptic deficit and social memory impairment driven by neurodevelopmental vulnerability of hippocampal parvalbumin interneurons

J Hazard Mater. 2024 Dec 16:485:136893. doi: 10.1016/j.jhazmat.2024.136893. Online ahead of print.

Authors

Affiliations

¹ Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA; NIEHS Environmental Toxicology Training Program, University of Texas Medical Branch, USA.
² Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
³ Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA; Inhalation Toxicology Core, University of Texas Medical Branch, USA.
⁵ Department of Chemistry, University of Texas, Austin, TX 78712, USA.
⁶ Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, USA.
⁷ Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: felaezza@utmb.edu.

PMID: 39706027
DOI: 10.1016/j.jhazmat.2024.136893

Abstract

Environmental exposure to pesticides at levels deemed safe by regulatory agencies has been linked to increased risk for neurodevelopmental disorders. Yet, the mechanisms linking exposure to these disorders remain unclear. Here, we show that maternal exposure to the pesticide deltamethrin (DM) at the no observed adverse effect level (NOAEL) disrupts long-term potentiation (LTP) in the hippocampus of adult male offspring three months after exposure, a phenotype absent in female offspring. Clonazepam, a GABAa receptor agonist, rescued this deficit, indicating impaired hippocampal GABAergic signaling. Recordings from CA1 pyramidal neurons, complemented by MALDI mass spectrometry imaging, showed an imbalance in excitatory/inhibitory tone. Using a combination of parvalbumin (PV)-Cre transgenic mice and hippocampal injection of designer receptors exclusively activated by designer drugs (DREADDs), we show that developmental DM exposure reduces hippocampal PV interneuron intrinsic firing. DREADD activation rescued both PV interneuron firing and LTP deficits. Complementary behavioral experiments revealed a deficit in social memory, a behavior relevant to autism spectrum disorder (ASD) symptomatology, which was restored by DREADD activation. Overall, these results establish a novel mechanistic link between maternal exposure to DM at the NOAEL and known cellular, circuital, and behavioral vulnerabilities, indicating it is a potential driver in the exposome of ASD.

Keywords: Autism Spectrum Disorder; Chemogenetic Receptors; E/I Tone; Exposome; Neurodevelopmental Toxicology; Social Dysfunction.