A myelin-related transcriptomic profile is shared by Pitt-Hopkins syndrome models and human autism spectrum disorder.

Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt-Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.

Autocrine boost of NMDAR current in hippocampal CA1 pyramidal neurons by a PMCA-dependent, perisynaptic, extracellular pH shift.

The plasma membrane Ca(2+)-ATPase (PMCA) is found near postsynaptic NMDARs. This transporter is a Ca(2+)-H(+) exchanger that raises cell surface pH. We tested whether the PMCA acts in an autocrine fashion to boost pH-sensitive, postsynaptic NMDAR currents. In mouse hippocampal slices, NMDAR EPSCs in a singly activated CA1 pyramidal neuron were reduced when buffering was augmented by exogenous carbonic anhydrase (XCAR). This effect was blocked by the enzyme inhibitor benzolamide and mimicked by the addition of HEPES buffer. Similar EPSC reduction occurred when PMCA activation was prevented by dialysis of BAPTA or the PMCA inhibitor carboxyeosin. Using HEPES, BAPTA, or carboxyeosin, the effect of XCAR was completely occluded. XCAR similarly curtailed NMDAR EPSCs of minimal amplitude, but had no effect on small AMPAR responses. These results indicate that a significant fraction of the postsynaptic NMDAR current is reliant on a perisynaptic extracellular alkaline shift generated by the PMCA.

GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current.

The CB(1) cannabinoid receptor mediates many of the psychoactive effects of Delta(9)THC, the principal active component of cannabis. However, ample evidence suggests that additional non-CB(1)/CB(2) receptors may contribute to the behavioral, vascular, and immunological actions of Delta(9)THC and endogenous cannabinoids. Here, we provide further evidence that GPR55, a G protein-coupled receptor, is a cannabinoid receptor. GPR55 is highly expressed in large dorsal root ganglion neurons and, upon activation by various cannabinoids (Delta(9)THC, the anandamide analog methanandamide, and JWH015) increases intracellular calcium in these neurons. Examination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calcium increase to involve G(q), G(12), RhoA, actin, phospholipase C, and calcium release from IP(3)R-gated stores. GPR55 activation also inhibits M current. These results establish GPR55 as a cannabinoid receptor with signaling distinct from CB(1) and CB(2).

Identification of a developmentally regulated striatum-enriched zinc-finger gene, Nolz-1, in the mammalian brain.

Neural information processed through the striatum of the basal ganglia is crucial for sensorimotor and psychomotor functions. Genes that are highly expressed in the striatum during development may be involved in neural development and plasticity in the striatum. We report in the present study the identification of a previously uncharacterized mammalian member of the nocA/elB/tlp-1 family, Nolz-1, that is preferentially expressed at high levels in the developing striatum. Nolz-1 mRNA was expressed as soon as striatal anlage began to form at embryonic day 13 in the rat. Nolz-1 mRNA was predominantly expressed in the lateral ganglionic eminence (striatal primordium) and was nearly absent in the adjacent structures of the medial ganglionic eminence and the cerebral cortex. Moreover, Nolz-1 was highly expressed in the subventricular zone of the lateral ganglionic eminence and was colocalized with the early neuronal differentiation markers of TuJ1 and Isl1 and the projection neuron marker of DARPP-32, suggesting that Nolz-1 was expressed in differentiating progenitors of striatal projection neurons. A time course study showed that Nolz-1 mRNA was developmentally regulated, as its expression was down-regulated postnatally with low levels remaining in the ventral striatum at adulthood. As the tagged Nolz-1 protein was localized in the nucleus, Nolz-1 may function as transcriptional regulator. In a model system for neural differentiation, Nolz-1 mRNA was dramatically induced on neural induction of P19 embryonal carcinoma cells by retinoic acid, suggesting that Nolz-1 activation may be involved in neural differentiation. Our study suggests that Nolz-1 is preferentially expressed in differentiating striatal progenitors and may be engaged in the genetic program for controlling striatal development.