Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a non-retrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. Synaptic endocannabinoid signaling is thus mechanistically more complex and diverse than originally thought. In this review, we focus on new advances in endocannabinoid signaling and highlight their role as potent regulators of synaptic function in the mammalian brain.

Summary Long-term changes of neurotransmitter release are critical for proper brain function. However, the molecular mechanisms underlying these changes are poorly understood. While protein synthesis is crucial for the consolidation of postsynaptic plasticity, whether and how protein synthesis regulates presynaptic plasticity in the mature mammalian brain remains unclear. Here, using paired whole-cell recordings in rodent hippocampal slices, we report that presynaptic protein synthesis is required for long-term, but not short-term, plasticity of GABA release from type-1 cannabinoid receptor (CB1)-expressing axons. This long-term depression of inhibitory transmission (iLTD) involves cap-dependent protein synthesis in presynaptic interneuron axons but not somata. Translation is required during the induction, but not maintenance, of iLTD. Mechanistically, CB1 activation enhances protein synthesis via the mTOR pathway. Furthermore, using super-resolution STORM microscopy, we revealed eukaryotic ribosomes in CB1-expressing axon terminals. These findings suggest that presynaptic local protein synthesis controls neurotransmitter release during long-term plasticity in the mature mammalian brain.

Long-lasting changes of brain function in response to experience rely on diverse forms of activity-dependent synaptic plasticity. Chief among them are long-term potentiation and long-term depression of neurotransmitter release, which are widely expressed by excitatory and inhibitory synapses throughout the central nervous system and can dynamically regulate information flow in neural circuits. This review article explores recent advances in presynaptic long-term plasticity mechanisms and contributions to circuit function. Growing evidence indicates that presynaptic plasticity may involve structural changes, presynaptic protein synthesis, and transsynaptic signaling. Presynaptic long-term plasticity can alter the short-term dynamics of neurotransmitter release, thereby contributing to circuit computations such as novelty detection, modifications of the excitatory/inhibitory balance, and sensory adaptation. In addition, presynaptic long-term plasticity underlies forms of learning and its dysregulation participates in several neuropsychiatric conditions, including schizophrenia, autism, intellectual disabilities, neurodegenerative diseases, and drug abuse.

Proper synaptic function requires the spatial and temporal compartmentalization of RNA metabolism via transacting RNA-binding proteins (RBPs). Loss of RBP activity leads to abnormal posttranscriptional regulation and results in diverse neurological disorders with underlying deficits in synaptic morphology and transmission. Functional loss of the 68-kDa RBP Src associated in mitosis (Sam68) is associated with the pathogenesis of the neurological disorder fragile X tremor/ataxia syndrome. Sam68 binds to the mRNA of β-actin (actb), an integral cytoskeletal component of dendritic spines. We show that Sam68 knockdown or disruption of the binding between Sam68 and its actb mRNA cargo in primary hippocampal cultures decreases the amount of actb mRNA in the synaptodendritic compartment and results in fewer dendritic spines. Consistent with these observations, we find that Sam68-KO mice have reduced levels of actb mRNA associated with synaptic polysomes and diminished levels of synaptic actb protein, suggesting that Sam68 promotes the translation of actb mRNA at synapses in vivo. Moreover, genetic knockout of Sam68 or acute knockdown in vivo results in fewer excitatory synapses in the hippocampal formation as assessed morphologically and functionally. Therefore, we propose that Sam68 regulates synapse number in a cell-autonomous manner through control of postsynaptic actb mRNA metabolism. Our research identifies a role for Sam68 in synaptodendritic posttranscriptional regulation of actb and may provide insight into the pathophysiology of fragile X tremor/ataxia syndrome.

Two-photon microscopy is widely used to investigate brain function across multiple spatial scales. However, measurements of neural activity are compromised by brain movement in behaving animals. Brain motion-induced artefacts are typically corrected using post-hoc processing of 2D images, but this approach is slow and does not correct for axial movements. Moreover, the deleterious effects of brain movement on high speed imaging of small regions of interest and photostimulation cannot be corrected post-hoc . To address this problem, we combined random access 3D laser scanning using an acousto-optic lens and rapid closed-loop FPGA processing to track 3D brain movement and correct motion artifacts in real-time at up to 1 kHz. Our recordings from synapses, dendrites and large neuronal populations in behaving mice and zebrafish demonstrate real-time movement corrected 3D two-photon imaging with sub-micrometer precision.