BCL7A-containing SWI/SNF/BAF complexes modulate mitochondrial bioenergetics during neural progenitor differentiation.

Mammalian SWI/SNF/BAF chromatin remodeling complexes influence cell lineage determination. While the contribution of these complexes to neural progenitor cell (NPC) proliferation and differentiation has been reported, little is known about the transcriptional profiles that determine neurogenesis or gliogenesis. Here, we report that BCL7A is a modulator of the SWI/SNF/BAF complex that stimulates the genome-wide occupancy of the ATPase subunit BRG1. We demonstrate that BCL7A is dispensable for SWI/SNF/BAF complex integrity, whereas it is essential to regulate Notch/Wnt pathway signaling and mitochondrial bioenergetics in differentiating NPCs. Pharmacological stimulation of Wnt signaling restores mitochondrial respiration and attenuates the defective neurogenic patterns observed in NPCs lacking BCL7A. Consistently, treatment with an enhancer of mitochondrial biogenesis, pioglitazone, partially restores mitochondrial respiration and stimulates neuronal differentiation of BCL7A-deficient NPCs. Using conditional BCL7A knockout mice, we reveal that BCL7A expression in NPCs and postmitotic neurons is required for neuronal plasticity and supports behavioral and cognitive performance. Together, our findings define the specific contribution of BCL7A-containing SWI/SNF/BAF complexes to mitochondria-driven NPC commitment, thereby providing a better understanding of the cell-intrinsic transcriptional processes that connect metabolism, neuronal morphogenesis, and cognitive flexibility.

Multi-omics identify xanthine as a pro-survival metabolite for nematodes with mitochondrial dysfunction.

Aberrant mitochondrial function contributes to the pathogenesis of various metabolic and chronic disorders. Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Using an unbiased multi-omics approach, we report here that IIS inhibition reduces protein synthesis and favors catabolism in mitochondrial deficient Caenorhabditis elegans We unveil that the lifespan extension does not occur through the restoration of mitochondrial respiration, but as a consequence of an ATP-saving metabolic rewiring that is associated with an evolutionarily conserved phosphoproteome landscape. Furthermore, we identify xanthine accumulation as a prominent downstream metabolic output of IIS inhibition. We provide evidence that supplementation of FDA-approved xanthine derivatives is sufficient to promote fitness and survival of nematodes carrying mitochondrial lesions. Together, our data describe previously unknown molecular components of a metabolic network that can extend the lifespan of short-lived mitochondrial mutant animals.

DOI-induced deficits in prepulse inhibition in Wistar rats are reversed by mGlu2/3 receptor stimulation.

Prepulse inhibition (PPI) of the acoustic startle response (ASR) provides a measure of sensorimotor gating mechanisms that are impaired in schizophrenia patients. Interactions of the serotonin (5-hydroxytryptamine, 5-HT) and glutamatergic systems, especially via the 5-HT(2A) receptor subtype, have been implicated in the regulation of PPI. The present study investigated the involvement of interactions between 5-HT(2A) and metabotropic glutamate (mGlu)2/3 receptors in modulating PPI in Wistar and Lister Hooded rats. Systemic administration of the 5-HT(2A/2C) receptor agonist DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride; 3mg/kg) reduced PPI and ASR magnitude in Wistar but not in Lister Hooded rats. In Wistar rats, pre-treatment with the mGlu2/3 receptor agonist LY379268 (1mg/kg) attenuated the DOI-induced disruption of PPI as well as the DOI-elicited reductions of ASR magnitude. LY379268 itself did not alter PPI in both strains and only slightly increased ASR magnitudes in Wistar rats. Taken together, these findings support the notion of functionally antagonistic interactions between 5-HT(2A) and mGlu2/3 which might be involved in regulating sensorimotor gating mechanisms. Additionally, the data suggest that stimulation of mGlu2/3 receptors may be useful to ameliorate sensorimotor gating deficits resulting from an overstimulation of 5-HT(2A) receptors.

Neuregulin 1 hypomorphic mutant mice: enhanced baseline locomotor activity but normal psychotropic drug-induced hyperlocomotion and prepulse inhibition regulation.

Neuregulin 1 (Nrg1) has been widely recognized as a candidate gene for schizophrenia. This study therefore investigated mice heterozygous for a mutation in the transmembrane domain of this trophic factor (Nrg1+/- mice) in a number of behavioural test systems with relevance to schizophrenia, including psychotropic drug-induced locomotor hyperactivity and prepulse inhibition (PPI) of startle. Baseline locomotor activity in the open field or in photocell cages was slightly, but significantly enhanced in Nrg1+/- mice compared to wild-type littermate controls at age 12-16 wk, but not at age 6 months. The ability of amphetamine, phencyclidine (PCP) or MK-801 to induce locomotor hyperactivity was not significantly different between the genotypes. There was no difference in baseline PPI, startle or startle habituation and there was no difference in the effect of apomorphine, amphetamine or MK-801 on any of these parameters. Only treatment with the 5-HT1A receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) showed a differential effect between genotypes, with a disruption of PPI occurring in Nrg1+/- mice compared to no effect in wild-type controls. This treatment also induced a significant reduction of startle which could have influenced the result. The density of dopamine D2 receptors in the forebrain and of 5-HT1A receptors in the hippocampus and raphe nuclei was not different between Nrg1+/- mice and controls. These studies add to the knowledge about behavioural effects in this mouse model of impaired Nrg1 function and suggest that a number of the behavioural tests with relevance to schizophrenia are normal in these mice.