Glyphosate impairs both structure and function of GABAergic synapses in hippocampal neurons

• Published in: Neuropharmacology Vol. 262; p. 110183
• Main Authors: Chiantia, Giuseppe, Comai, Debora, Hidisoglu, Enis, Gurgone, Antonia, Franchino, Claudio, Carabelli, Valentina, Marcantoni, Andrea, Giustetto, Maurizio
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2025
• Subjects: GABAergic synapses; Gephyrin; Glyphosate; Hippocampal neurons; Immunocytochemistry; Patch-clamp; GABAergic synapses; Hippocampal neurons; Patch-clamp; Immunocytochemistry; Glyphosate; Gephyrin; immunocytochemistry; gephyrin; patch-clamp; hippocampal neurons
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2024.110183

Glyphosate (Gly) is a broad-spectrum herbicide responsible for the inhibition of the enzyme 5-enolpyruvylshikimate-3-phosphate synthase known to be expressed exclusively in plants and not in animals. For decades Gly has been thought to be ineffective in mammals, including humans, until it was demonstrated that rodents treated with the Gly-based herbicide Roundup showed reduced content of neurotransmitters (e.g., serotonin, dopamine, norepinephrine, and acetylcholine), increased oxidative stress in the brain associated with anxiety and depression-like behaviors and learning and memory deficits. Despite compelling evidence pointing to a neurotoxic effect of Gly, an in-depth functional description of its effects on synaptic transmission is still lacking. To investigate the synaptic alterations dependent on Gly administration we performed whole-cell patch-clamp recordings and immunocytochemistry on mouse primary cultured hippocampal neurons. Our findings reveal that 30 min incubation of Gly at the acceptable daily intake dose severely impaired inhibitory GABAergic synapses. Further analysis pointed out that Gly decreased the number of postsynaptic GABAA receptors and reduced the amplitude of evoked inhibitory postsynaptic currents, the readily releasable pool size available for synchronous release and the quantal size. Finally, a decreased number of release sites has been observed. Consistently, morphological analyses showed that the density of both pre- and post-synaptic inhibitory compartments decorating pyramidal cell dendrites was reduced by Gly. In conclusion, our experiments define for the first time the effects induced by Gly on GABAergic synapses, and reveal that Gly significantly impairs both pre- and postsynaptic mechanisms. •Glyphosate (Gly) is the active component of the most used herbicide in the world.•The impact of Gly on GABAergic synaptic transmission and connectivity is unknown.•Gly impairs both pre- and postsynaptic GABAergic responses in hippocampal neurons.•Both density and size of GABAergic synaptic contacts are altered by Gly.•These experiments show for the first time that Gly can alter GABAergic inhibition.