Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors. However, the role of orexin signaling in neural plasticity is poorly understood. The present study shows that in vitro application of orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses. Furthermore, in vivo administration of an orexin 1 receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.

One of the defining features of the nervous system is its ability to modify synaptic strength in an experience-dependent manner. Chronic elevation or reduction of network activity activates compensatory mechanisms that modulate synaptic strength in the opposite direction (i.e. reduced network activity leads to increased synaptic strength), a process called homeostatic synaptic plasticity. Among the many mechanisms that mediate homeostatic synaptic plasticity, retinoic acid (RA) has emerged as a novel signaling molecule that is critically involved in homeostatic synaptic plasticity induced by blockade of synaptic activity. In neurons, silencing of synaptic transmission triggers RA synthesis. RA then acts at synapses by a non-genomic mechanism that is independent of its well-known function as a transcriptional regulator, but operates through direct activation of protein translation in neuronal dendrites. Protein synthesis is activated by RA-binding to its receptor RARα, which functions locally in dendrites in a non-canonical manner as an RNA-binding protein that mediate RA’s effect on translation. The present review will discuss recent progress in our understanding of the novel role of RA, which led to the identification of RA as a critical synaptic signaling molecule that mediates activity-dependent regulation of protein synthesis in neuronal dendrites. This article is part of a Special Issue entitled ‘Homeostatic Plasticity’.

In brain, properly balanced synaptic excitation and inhibition is critically important for network stability and efficient information processing. Here, we show that retinoic acid (RA), a synaptic signaling molecule whose synthesis is activated by reduced neural activity, induces rapid internalization of synaptic GABA A receptors in mouse hippocampal neurons, leading to significant reduction of inhibitory synaptic transmission. Similar to its action at excitatory synapses, action of RA at inhibitory synapses requires protein translation and is mediated by a nontranscriptional function of the RA-receptor RAR␣. Different from RA action at excitatory synapses, however, RA at inhibitory synapses causes a loss instead of the gain of a synaptic protein (i.e., GABA A Rs). Moreover, the removal of GABA A Rs from the synapses and the reduction of synaptic inhibition do not require the execution of RA's action at excitatory synapses (i.e., downscaling of synaptic inhibition is intact when upscaling of synaptic excitation is blocked). Thus, the action of RA at inhibitory and excitatory synapses diverges significantly after the step of RAR␣-mediated protein synthesis, and the regulations of GABA A R and AMPAR trafficking are independent processes. When both excitatory and inhibitory synapses are examined together in the same neuron, the synaptic excitation/ inhibition ratio is significantly enhanced by RA. Importantly, RA-mediated downscaling of synaptic inhibition is completely absent in Fmr1 knock-out neurons. Thus, RA acts as a central organizer for coordinated homeostatic plasticity in both excitatory and inhibitory synapses, and impairment of this overall process alters the excitatory/inhibitory balance of a circuit and likely represents a major feature of fragile X-syndrome.