A number of mutations in genes that encode ubiquitously expressed RNA-binding proteins cause tissue specific disease. Many of these diseases are neurological in nature revealing critical roles for this class of proteins in the brain. We recently identified mutations in a gene that encodes a ubiquitously expressed polyadenosine RNA-binding protein, ZC3H14 (Zinc finger CysCysCysHis domain-containing protein 14), that cause a nonsyndromic, autosomal recessive form of intellectual disability. This finding reveals the molecular basis for disease and provides evidence that ZC3H14 is essential for proper brain function. To investigate the role of ZC3H14 in the mammalian brain, we generated a mouse in which the first common exon of the ZC3H14 gene, exon 13 is removed (Zc3h14Δex13/Δex13) leading to a truncated ZC3H14 protein. We report here that, as in the patients, Zc3h14 is not essential in mice. Utilizing these Zc3h14Δex13/Δex13mice, we provide the first in vivo functional characterization of ZC3H14 as a regulator of RNA poly(A) tail length. The Zc3h14Δex13/Δex13 mice show enlarged lateral ventricles in the brain as well as impaired working memory. Proteomic analysis comparing the hippocampi of Zc3h14+/+ and Zc3h14Δex13/Δex13 mice reveals dysregulation of several pathways that are important for proper brain function and thus sheds light onto which pathways are most affected by the loss of ZC3H14. Among the proteins increased in the hippocampi of Zc3h14Δex13/Δex13 mice compared to control are key synaptic proteins including CaMK2a. This newly generated mouse serves as a tool to study the function of ZC3H14 in vivo.

Objective: The endocannabinoid system (ECS) is comprised of cannabinoid receptors 1 and 2 (CB1R and CB2R), endogenous ligands, and regulatory enzymes, and serves to regulate several important physiological functions throughout the brain and body. Recent evidence suggests that the ECS may be a promising target for the treatment of epilepsy, including epilepsy subtypes that arise from mutations in the voltage-gated sodium channel SCN1A. The objective of this study was to explore the effects of modulating CB2R activity on seizure susceptibility. Methods: We examined susceptibility to induced seizures using a number of paradigms in CB2R knockout mice (Cnr2 −/− ), and determined the effects of the CB2R agonist, JWH-133, and the CB2R antagonist, SR144528, on seizure susceptibility in wild-type mice. We also examined seizure susceptibility in Cnr2 mutants harboring the human SCN1A R1648H (RH) epilepsy mutation and performed Electroencephalography (EEG) analysis to determine whether the loss of CB2Rs would increase spontaneous seizure frequency in Scn1a RH mutant mice. Results: Both heterozygous (Cnr2 +/− ) and homozygous (Cnr2 −/− ) knockout mice exhibited increased susceptibility to pentylenetetrazole (PTZ)-induced seizures. The CB2R agonist JWH-133 did not significantly alter seizure susceptibility in wildtype mice; however, administration of the CB2R antagonist SR144528 resulted in increased susceptibility to PTZ-induced seizures. In offspring from a cross between the Cnr2 × RH lines, both Cnr2 and RH mutants were susceptible to PTZ-induced seizures; however, seizure susceptibility was not significantly increased in mutants expressing both mutations. No spontaneous seizures were observed in either RH or Cnr2/RH mutants during 336-504 hours of continuous EEG recordings. Significance: Our results demonstrate that reduced CB2R activity is associated with increased seizure susceptibility. CB2Rs might therefore provide a therapeutic target for the treatment of some forms of epilepsy. K E Y W O R D Scannabinoid 2 receptor, CB2R agonist, CB2R antagonist, SCN1A, seizure susceptibility 2360 | SHAPIRO et Al.

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Arboreal lifestyles represent common and major habitat shifts among snakes. Major habitat shifts are often facilitated by particular traits that confer advantages in the new environment. Although studies have examined the habits and characteristics of arboreal snakes at the level of individual species or small clades, a broad survey has never been performed across all snakes. We surveyed the literature to identify all known arboreal snakes and summarize their general characteristics. We then tested for associations between diversification rates and arboreal habits and reconstructed ancestral states using the hidden state speciation and extinction (HiSSE) approach. Finally, we tested for an association between body size and arboreality by fitting multi-peak Ornstein-Uhlenbeck models. We expected that transitions to an arboreal lifestyle might open new ecological opportunities, leading to increased diversification rates, and that different selective pressures for arboreal snakes might lead to changes in body size evolution. We found that generally, arboreal snakes are most frequently nocturnal, oviparous, reptile-eating, brown/banded/patterned snakes inhabiting the Neotropics (assessing each trait individually, not jointly) and that arboreality has no effect on rates of diversification. Ornstein-Uhlenbeck models showed that arboreal snakes tend to be longer than non-arboreal snakes, that rates of body size evolution are generally lower in arboreal snakes, and that arboreal body sizes are pulled more strongly towards their optimum than in non-arboreal snakes. These results suggest that morphological evolution is more constrained in arboreal snakes than in non-arboreal snakes.

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