Intracellular mGluR5 can mediate synaptic plasticity in the hippocampus

Area of Science:

• Neuroscience
• Molecular Biology
• Cellular Signaling

Background:

• Metabotropic glutamate receptor 5 (mGluR5) is crucial for neuronal function and synaptic transmission across the central nervous system.
• Previous studies identified intracellular mGluR5 signaling in the striatum, upregulating ERK1/2, Elk-1, and Arc.
• The localization and function of intracellular mGluR5 in hippocampal excitatory neurons remained largely unexplored.

Purpose of the Study:

• To investigate the presence and function of intracellular mGluR5 in rat CA1 hippocampal neurons.
• To determine if intracellular mGluR5 activation influences calcium signaling and synaptic plasticity in the hippocampus.

Main Methods:

• Utilized dissociated rat CA1 hippocampal cultures and acute slice preparations.
• Localized endogenous mGluR5 using immunofluorescence, observing colocalization with EAAT3 in the endoplasmic reticulum and nucleus.
• Employed pharmacological agents and sodium-free conditions to differentiate mGluR5 pools.
• Measured calcium (Ca2+) responses using calcium imaging.
• Assessed synaptic plasticity (LTD and LTP) via electrophysiological recordings in hippocampal slices.

Main Results:

• CA1 neurons express mGluR5 on both cell surface and intracellular membranes, including the ER and nucleus, colocalizing with EAAT3.
• Inhibition of EAAT3 or sodium deprivation impaired agonist uptake, indicating EAAT3's role in mGluR5 localization or function.
• Both cell surface and intracellular mGluR5 induced oscillatory Ca2+ responses, but intracellular activation uniquely triggered sustained, high-amplitude Ca2+ rises in dendrites.
• Glutamate uncaging on dendrites evoked local Ca2+ increases, even with inhibitors present, confirming intracellular signaling.
• Activation of intracellular mGluR5 alone induced both electrically and chemically induced long-term depression (LTD), but not long-term potentiation (LTP).

Conclusions:

• Intracellular mGluR5 is present and functional in hippocampal CA1 pyramidal neurons, distinct from cell surface signaling.
• Intracellular mGluR5 activation plays a significant role in regulating dendritic calcium dynamics.
• Intracellular mGluR5 signaling is sufficient to induce long-term depression, highlighting its physiological relevance in hippocampal synaptic plasticity.