Voltage tunes mGlu5 receptor function, impacting synaptic transmission.

BACKGROUND AND PURPOSE: Voltage sensitivity is a common feature of many membrane proteins, including some G-protein coupled receptors (GPCRs). However, the functional consequences of voltage sensitivity in GPCRs are not well understood. EXPERIMENTAL APPROACH: In this study, we investigated the voltage sensitivity of the post-synaptic metabotropic glutamate receptor mGlu5 and its impact on synaptic transmission. Using biosensors and electrophysiological recordings in non-excitable HEK293T cells or neurons. KEY RESULTS: We found that mGlu5 receptor function is optimal at resting membrane potentials. We observed that membrane depolarization significantly reduced mGlu5 receptor activation, Gq-PLC/PKC stimulation, Ca2+ release and mGlu5 receptor-gated currents through transient receptor potential canonical, TRPC6, channels or glutamate ionotropic NMDA receptors. Notably, we report a previously unknown activity of the NMDA receptor at the resting potential of neurons, enabled by mGlu5. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that mGlu5 receptor activity is directly regulated by membrane voltage which may have a significant impact on synaptic processes and pathophysiological functions.

Continuous low-level dietary exposure to glyphosate elicits dose and sex-dependent synaptic and microglial adaptations in the rodent brain.

Prolonged exposure to low levels of dietary contaminants is a context in modern life that could alter organ physiology gradually. Here, we aimed to investigate the impact of continuous exposure to acceptable daily intake (ADI) and non-observable adverse effect level (NOAEL) of glyphosate from gestation to adulthood using C57BL/6J mice and incorporating these levels into their food pellets. From adulthood, we analyzed neurophysiological and neuro-glia cellular adaptations in male and female animals. Using ex-vivo hippocampal slice electrophysiology, we found a reduced efficacy of Schaffer collateral-to-CA1 excitatory synapses in glyphosate-exposed dietary conditions, with ADI and NOAEL dose-dependent effects. Short-term facilitation of excitatory synaptic transmission was specifically increased in NOAEL conditions, with a predominant influence in males, suggesting a reduced probability of neurotransmitter release. Long-term synaptic potentiation (LTP) was decreased in NOAEL-exposed mice. Next, we explore whether these neurophysiological modifications are associated with neuro-glia changes in the somatosensory cortex and hippocampus. High-resolution confocal microscopy analyses unveil a dose-dependent increased density of excitatory Vglut1+ Homer1+ synapses. Microglial Iba1+ cells displayed a shortening of their ramifications, a sign of cellular reactivity that was more pronounced in males at NOAEL levels. The morphology of GFAP+ astrocytes was generally not modified. Finally, we asked whether mouse-specific cross-correlations exist among all data sets generated. This examination included the novel object recognition (NOR) test performed before ex vivo functional and immunohistochemical examinations. We report a negative linear regression between the number of synapses and NOR or LTP maintenance when plotting ADI and NOAEL datasets. These results outline synaptic and microglial cell adaptations resulting from prenatal and continuous dietary low levels of glyphosate, discernible in, but not limited to, adult males exposed to the NOAEL. We discuss the potential significance of these findings to real-world consumer situations and long-term brain resilience.