Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1–4 (CPEB1–4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.

Ischemic stroke is the second cause of mortality and the first cause of long-term disability constituting a serious socioeconomic burden worldwide. Approved treatments include thrombectomy and rtPA intravenous administration, which, despite their efficacy in some cases, are not suitable for a great proportion of patients. Glial cell-related therapies are progressively overcoming inefficient neuron-centered approaches in the preclinical phase. Exploiting the ability of microglia to naturally switch between detrimental and protective phenotypes represents a promising therapeutic treatment, in a similar way to what happens with astrocytes. However, the duality present in many of the roles of these cells upon ischemia poses a notorious difficulty in disentangling the precise pathways to target. Still, promoting M2/A2 microglia/astrocyte protective phenotypes and inhibiting M1/A1 neurotoxic profiles is globally rendering promising results in different in vivo models of stroke. On the other hand, described oligodendrogenesis after brain ischemia seems to be strictly beneficial, although these cells are the less studied players in the stroke paradigm and negative effects could be described for oligodendrocytes in the next years. Here, we review recent advances in understanding the precise role of mentioned glial cell types in the main pathological events of ischemic stroke, including inflammation, blood brain barrier integrity, excitotoxicity, reactive oxygen species management, metabolic support, and neurogenesis, among others, with a special attention to tested therapeutic approaches.

The disturbances of cellular proteostasis caused by the alteration in the ubiquitin‐proteasome system (UPS) have been proposed as a common mechanism underlying several neural pathologies that involve a neuro‐inflammatory process. As we have previously reported that the nucleotide receptor P2Y purinoceptor 2 (P2Y ₂ R) regulates the proteasomal catalytic activities, we wonder whether this receptor is involved in the UPS disturbances associated with the neuroinflammation process. With the use of mice expressing a UPS reporter [mice expressing the UPS reporter ubiquitin ^G76V ‐green fluorescent protein (UbGFP mice)], we found that LPS‐induced acute neuroinflammation status causes a UPS impairment in astrocytes and microglial cells by a mechanism dependent on P2Y ₂ R. In this line, LPS‐treated double transgenic UbGFP; P2Y ₂ R ^−/− mice did not present a UPS impairment in astrocytes or a social interaction deficit as severe as that observed in LPS‐treated UbGFP mice. In vivo administration of selective P2Y ₂ R agonist diuridine tetraphosphate reversed the UPS impairment completely in astrocytes and partially in microglial cells, promoting increased expression of the proteasomal β5 subunit by a mechanism dependent on the Src/ PI3K/ERK pathway. Altogether, our results suggest that LPS induces unbalanced proteostasis in astrocytes by blocking P2Y ₂ R. Finally, our findings point to the design of selective P2Y ₂ R agonist drugs as a new therapeutic approach to treat the neuroinflammatory status.—De Diego García, L., Sebastián‐Serrano, Á., Hernández, I. H., Pintor, J., Lucas, J. J., Díaz‐Hernández, M. The regulation of proteostasis in glial cells by nucleotide receptors is key in acute neuroinflammation. FASEB J. 32, 3020–3032 (2018). www.fasebj.org