Synaptic retinoic acid receptor signaling mediates mTOR-dependent metaplasticity that controls hippocampal learning

Abstract

Significance Homeostatic synaptic plasticity has long been considered an anti-Hebbian mechanism that maintains the brain’s network stability, prevents aberrant Hebbian plasticity, and sustains normal cognitive functions. However, evidence supporting this hypothesis is largely lacking. Using region-specific deletions of the retinoic acid receptor RARα, a key mediator of homeostatic synaptic plasticity, we show that experience of an enriched environment (EE) engages homeostatic synaptic plasticity in hippocampal neurons in an RARα-dependent manner. EE experience in mice with deletion of RARα in the hippocampus caused runaway long-term potentiation (LTP), enhanced contextual memory, and reduced cognitive flexibility by hyperactivating mammalian target of rapamycin (mTOR) signaling. Treatment with the mTOR inhibitor rapamycin during an EE experience reversed both runaway LTP and enhanced learning, demonstrating a close functional interaction between Hebbian and homeostatic plasticity. Homeostatic synaptic plasticity is a stabilizing mechanism engaged by neural circuits in response to prolonged perturbation of network activity. The non-Hebbian nature of homeostatic synaptic plasticity is thought to contribute to network stability by preventing “runaway” Hebbian plasticity at individual synapses. However, whether blocking homeostatic synaptic plasticity indeed induces runaway Hebbian plasticity in an intact neural circuit has not been explored. Furthermore, how compromised homeostatic synaptic plasticity impacts animal learning remains unclear. Here, we show in mice that the experience of an enriched environment (EE) engaged homeostatic synaptic plasticity in hippocampal circuits, thereby reducing excitatory synaptic transmission. This process required RARα, a nuclear retinoic acid receptor that doubles as a cytoplasmic retinoic acid-induced postsynaptic regulator of protein synthesis. Blocking RARα-dependent homeostatic synaptic plasticity during an EE experience by ablating RARα signaling induced runaway Hebbian plasticity, as evidenced by greatly enhanced long-term potentiation (LTP). As a consequence, RARα deletion in hippocampal circuits during an EE experience resulted in enhanced spatial learning but suppressed learning flexibility. In the absence of RARα, moreover, EE experience superactivated mammalian target of rapamycin (mTOR) signaling, causing a shift in protein translation that enhanced the expression levels of AMPA-type glutamate receptors. Treatment of mice with the mTOR inhibitor rapamycin during an EE experience not only restored normal AMPA-receptor expression levels but also reversed the increases in runaway Hebbian plasticity and learning after hippocampal RARα deletion. Thus, our findings reveal an RARα- and mTOR-dependent mechanism by which homeostatic plasticity controls Hebbian plasticity and learning.