Influence of Nanomolar Deltamethrin on the Hallmarks of Primary Cultured Cortical Neuronal Network and the Role of Ryanodine Receptors

• Published in: Environmental health perspectives 2019-06, Vol.127 (6), p.67003
• Main Authors: Zheng, Jing, Yu, Yiyi, Feng, Wei, Li, Jing, Liu, Ju, Zhang, Chunlei, Dong, Yao, Pessah, Isaac N, Cao, Zhengyu
• Format: Article
• Language: English
• Subjects: Acids; Animals; Attention deficit hyperactivity disorder; Axons - drug effects; Calcium - metabolism; Calcium channels; Cells, Cultured; Channel gating; Channel opening; Channels; Complexity; Deactivation; Deltamethrin; Dendritic structure; Development and progression; Electric potential; Endoplasmic reticulum; Female; Firing pattern; Gene expression; Health aspects; Inactivation; Insect control; Insecticides; Insecticides - toxicity; Insects; Isoforms; Kinases; Kinetics; Male; Measurement methods; Metabolites; Mice, Inbred C57BL; Mice, Knockout; Microelectrodes; Morphology; Network formation; Neural circuitry; Neural networks; Neuronal Plasticity - drug effects; Neurons; Neurons - drug effects; Neurotoxicity; Neurotoxicity syndromes; Nitriles - toxicity; Oscillations; Perinatal exposure; Pesticides; Physiological aspects; Pyrethrins - toxicity; Pyrethroids; Receptors; Risk factors; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptors; Voltage; Womens health
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp4583

The pyrethroid deltamethrin (DM) is broadly used for insect control. Although DM hyperexcites neuronal networks by delaying inactivation of axonal voltage-dependent [Formula: see text] channels, this mechanism is unlikely to mediate neurotoxicity at lower exposure levels during critical perinatal periods in mammals. We aimed to identify mechanisms by which acute and subchronic DM altered axonal and dendritic growth, patterns of synchronous [Formula: see text] oscillations (SCOs), and electrical spike activity (ESA) functions critical to neuronal network formation. Measurements of SCOs using [Formula: see text] imaging, ESA using microelectrode array (MEA) technology, and dendritic complexity using Sholl analysis were performed in primary murine cortical neurons from wild-type (WT) and/or ryanodine receptor 1 ([Formula: see text]) mice between 5 and 14 d in vitro (DIV). [Formula: see text] binding analysis and a single-channel voltage clamp were utilized to measure engagement of RyRs as a direct target of DM. Neuronal networks responded to DM ([Formula: see text]) as early as 5 DIV, reducing SCO amplitude and depressing ESA and burst frequencies by 60-70%. DM ([Formula: see text]) enhanced axonal growth in a nonmonotonic manner. [Formula: see text] enhanced dendritic complexity. DM stabilized channel open states of RyR1, RyR2, and cortical preparations expressing all three isoforms. DM ([Formula: see text]) altered gating kinetics of RyR1 channels, increasing mean open time, decreasing mean closed time, and thereby enhancing overall open probability. SCO patterns from cortical networks expressing [Formula: see text] were more responsive to DM than WT. [Formula: see text] neurons showed inherently longer axonal lengths than WT neurons and maintained less length-promoting responses to nanomolar DM. Our findings suggested that RyRs were sensitive molecular targets of DM with functional consequences likely relevant for mediating abnormal neuronal network connectivity in vitro. https://doi.org/10.1289/EHP4583.