Enhanced mGlu5 Signaling in Excitatory Neurons Promotes Rapid Antidepressant Effects via AMPA Receptor Activation

🥇 Top 1% JournalAug 18, 2019Neuron

Stronger mGlu5 signaling in excitatory brain cells may speed up antidepressant effects through AMPA receptor activation

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Abstract

Intravenous injection of TAT-Homer1a elicits rapid antidepressant effects.

Mimicking Homer1a upregulation is associated with fast-acting antidepressant effects.
TAT-Homer1a enhances mGlu5 signaling, which may increase mTOR pathway activity.
This treatment upregulates synaptic AMPA receptor expression and activity.
The antidepressant effects depend on mGlu5 activation in specific excitatory neurons.
TAT-fused peptides that modulate mGlu5 and AMPA receptor activity could represent a novel approach for antidepressant treatment.

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Conventional antidepressants have limited efficacy and many side effects, highlighting the need for fast-acting and specific medications. Induction of the synaptic protein Homer1a mediates the effects of different antidepressant treatments, including the rapid action of ketamine and sleep deprivation (SD). We show here that mimicking Homer1a upregulation via intravenous injection of cell-membrane-permeable TAT-Homer1a elicits rapid antidepressant effects in various tests. Similar to ketamine and SD, in vitro and in vivo application of TAT-Homer1a enhances mGlu5 signaling, resulting in increased mTOR pathway phosphorylation, and upregulates synaptic AMPA receptor expression and activity. The antidepressant action of SD and Homer1a induction depends on mGlu5 activation specifically in excitatory CaMK2a neurons and requires enhanced AMPA receptor activity, translation, and trafficking. Moreover, our data demonstrate a pronounced therapeutic potential of different TAT-fused peptides that directly modulate mGlu5 and AMPA receptor activity and thus might provide a novel strategy for rapid and effective antidepressant treatment.

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