Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation. These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.

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Highlights d The entire tail of stargazin binds to PSD-95 with high affinity and specificity d Stargazin/PSD-95 complex form condensed assembly via phase separation d Other TARPs and MAGUKs interact with each other like stargazin/PSD-95 does d Stargazin/PSD-95 phase separation is required for AMPAR synaptic transmission

Background: CB 2 cannabinoid receptors promote neural progenitor cell proliferation. Results: CB 2 receptors induce neural progenitor cell proliferation and neurogenesis via activation of mTORC1 signaling. Conclusion: CB 2 receptor/mTORC1-induced neural progenitor proliferation is relevant under physiological and pathological conditions such as cortical development and excitotoxicity-induced adult hippocampal neurogenesis. Significance: Nonpsychotomimetic CB 2 receptor-selective ligands are promising molecules to manipulate neurogenesis.

The CB 1 cannabinoid receptor, the main target of Δ 9 -tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB 1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB 1 receptor genetic ablation, and CB 1 -null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB 1 expression-rescue strategy in a CB 1 -null background. Early and selective CB 1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB 1 -null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB 1 -dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB 1 signaling.R ecreational cannabis consumption during pregnancy can exert deleterious consequences in the progeny, including anxiety, depression, psychosis risk, and cognitive and social impairments (1, 2). In the last two decades, important advances in our understanding of the endocannabinoid system have paved the way to elucidate the particular neurobiological substrates responsible for some cannabinoid-induced neurological alterations in adult animals and humans (3). The currently accepted scenario is that the CB 1 cannabinoid receptor (CB 1 R), the main target of marijuana-derived cannabinoids, is located presynaptically and, upon engagement by endocannabinoids [2-arachidonoylglycerol (2-AG) and anandamide], can act as a key neuromodulatory and plasticity-tuning signaling platform at many different mature synapses (4). In fact, CB 1 R constitutes one of the most abundant and functionally relevant G proteincoupled receptors in several regions of the adult mammalian brain (3, 4).Manipulation of CB 1 R function in animal models, either directly or indirectly, by modulating 2-AG or anandamide levels through the main endocannabinoid-synthesi...

CaMKII is one of the most studied synaptic proteins, but many critical issues regarding its role in synaptic function remain unresolved. Using a CRISPR-based system to delete CaMKII and replace it with mutated forms in single neurons, we have rigorously addressed its various synaptic roles. In brief, basal AMPAR and NMDAR synaptic transmission both require CaMKIIα, but not CaMKIIβ, indicating that, even in the adult, synaptic transmission is determined by the ongoing action of CaMKIIα. While AMPAR transmission requires kinase activity, NMDAR transmission does not, implying a scaffolding role for the CaMKII protein instead. LTP is abolished in the absence of CaMKIIα and/or CaMKIIβ and with an autophosphorylation impaired CaMKIIα (T286A). With the exception of NMDAR synaptic currents, all aspects of CaMKIIα signaling examined require binding to the NMDAR, emphasizing the essential role of this receptor as a master synaptic signaling hub.

The amino-terminal domain (ATD) of AMPA receptors (AMPARs) accounts for approximately 50% of the protein, yet its functional role, if any, remains a mystery. We have discovered that the translocation of surface GluA1, but not GluA2, AMPAR subunits to the synapse requires the ATD. GluA1A2 heteromers in which the ATD of GluA1 is absent fail to translocate, establishing a critical role of the ATD of GluA1. Inserting GFP into the ATD interferes with the constitutive synaptic trafficking of GluA1, but not GluA2, mimicking the deletion of the ATD. Remarkably, long-term potentiation (LTP) can override the masking effect of the GFP tag. GluA1, but not GluA2, lacking the ATD fails to show LTP. These findings uncover a role for the ATD in subunit-specific synaptic trafficking of AMPARs, both constitutively and during plasticity. How LTP, induced postsynaptically, engages these extracellular trafficking motifs and what specific cleft proteins participate in the process remain to be elucidated.

The proneural factor Ascl1 controls multiple steps of neurogenesis in the embryonic brain, including progenitor division and neuronal migration. Here we show that Cenpj, also known as CPAP, a microcephaly gene, is a transcriptional target of Ascl1 in the embryonic cerebral cortex. We have characterized the role of Cenpj during cortical development by in utero electroporation knockdown and found that silencing Cenpj in the ventricular zone disrupts centrosome biogenesis and randomizes the cleavage plane orientation of radial glia progenitors. Moreover, we show that downregulation of Cenpj in post-mitotic neurons increases stable microtubules and leads to slower neuronal migration, abnormal centrosome position and aberrant neuronal morphology. Moreover, rescue experiments shows that Cenpj mediates the role of Ascl1 in centrosome biogenesis in progenitor cells and in microtubule dynamics in migrating neurons. These data provide insights into genetic pathways controlling cortical development and primary microcephaly observed in humans with mutations in Cenpj.