A final step of neurogenesis is the maturation of young neurons, which is regulated by complex mechanisms and dysregulation of this process is frequently found in neurodevelopmental disorders. MicroRNAs have been implicated in several steps of neuronal maturation including dendritic and axonal growth, spine development, and synaptogenesis. We demonstrate that one brain-enriched microRNA, miR-137, has a significant role in regulating neuronal maturation. Overexpression of miR-137 inhibits dendritic morphogenesis, phenotypic maturation, and spine development both in brain and cultured primary neurons. On the other hand, a reduction in miR-137 had opposite effects. We further show that miR-137 targets the Drosophila Mib1 protein through the conserved target site located in the 3′ untranslated region of Mib1 mRNA. Mib1 is an ubiquitin ligase known to be important for neurodevelopment. We show that exogenously expressed Mib1 could partially rescue the phenotypes associated with miR-137 overexpression. These results demonstrate a novel miRNA-mediated mechanism involving miR-137 and Mib1 that function to regulate neuronal maturation and dendritic morphogenesis during development.

Summary Methyl-CpG binding protein 1 (MBD1) regulates gene expression via a DNA methylation-mediated epigenetic mechanism. We have previously demonstrated that MBD1 deficiency impairs adult neural stem/progenitor cell (aNSC) differentiation and neurogenesis, but the underlying mechanism was unclear. Here we show that MBD1 regulates the expression of several microRNAs in aNSCs, and specifically that miR-184 is directly repressed by MBD1. High levels of miR-184 promoted proliferation but inhibited differentiation of aNSCs, whereas inhibition of miR-184 rescued the phenotypes associated with MBD1 deficiency. We further found that miR-184 regulates the expression of Numblike (Numbl), a known regulator of brain development, by binding to the 3′-UTR of Numbl mRNA and affecting its translation. Expression of exogenous Numbl could rescue the aNSC defects that result from either miR-184 overexpression or MBD1 deficiency. Therefore MBD1, miR-184, and Numbl form a regulatory network that helps control the balance between proliferation and differentiation of aNSCs.

Summary Alzheimer’s disease (AD) is the most common cause of dementia among older people. There are no effective medications currently available to prevent and treat AD and halt disease progression. Monoacylglycerol lipase (MAGL) is the primary enzyme metabolizing the endocannabinoid 2-arachidonoylglycerol in the brain. We show here that inactivation of MAGL robustly suppressed production and accumulation of β-amyloid (Aβ) associated with reduced expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in a mouse model of AD. MAGL inhibition also prevented neuroinflammation, decreased neurodegeneration, maintained integrity of hippocampal synaptic structure and function, and improved long-term synaptic plasticity, spatial learning and memory in AD animals. While the molecular mechanisms underlying MAGL inhibition-produced beneficial effects remain to be determined, our results suggest that MAGL, which regulates endocannabinoid and prostaglandin signaling, contributes to pathogenesis and neuropathology of AD and thus is a promising therapeutic target for the prevention and treatment of AD.

SUMMARY Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids, in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G-protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks down-regulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ9-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.

Abnormal accumulation of ␤-amyloid (A␤) is the major neuropathological hallmark of Alzheimer's disease (AD). However, the mechanisms underlying aberrant A␤ formation in AD remain unclear. We showed previously that inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, robustly reduces A␤ by inhibiting ␤-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme responsible for A␤ formation. However, the molecular mechanisms responsible for suppression of BACE1 by inhibition of 2-AG metabolism are largely unknown. We demonstrate here that expression of the noncoding small RNA miR-188-3p that targets BACE1 was significantly downregulated both in the brains of AD humans and APP transgenic (TG) mice, a mouse model of AD. The downregulated miR-188-3p expression was restored by MAGL inhibition. Overexpression of miR-188-3p in the hippocampus reduced BACE1, A␤, and neuroinflammation and prevented deteriorations in hippocampal basal synaptic transmission, long-term potentiation, spatial learning, and memory in TG mice. 2-AG-induced suppression of BACE1 was prevented by miR-188-3p loss of function. Moreover, miR-188-3p expression was upregulated by 2-AG or peroxisome proliferator-activated receptor-␥ (PPAR␥) agonists and suppressed by PPAR␥ antagonism or NF-B activation. Reducing A␤ and neuroinflammation by MAGL inhibition was occluded by PPAR␥ antagonism. In addition, BACE1 suppression by 2-AG and PPAR␥ activation was eliminated by knockdown of NF-B. Our study provides a novel molecular mechanism underlying improved synaptic and cognitive function in TG mice by 2-AG signaling, which upregulates miR-188-3p expression through PPAR␥ and NF-B signaling pathway, resulting in suppressions of BACE1 expression and A␤ formation.