Blue light-induced transcription in Neurospora crassa is regulated by the White Collar-1 (WC-1) photoreceptor. We report that residue K14 of histone H3 associated with the light-inducible albino-3 (al-3) promoter becomes transiently acetylated after photoinduction. This acetylation depends on WC-1. The relevance of this chromatin modification was directly evaluated in vivo by construction of a Neurospora strain with a mutated histone H3 gene (hH3 K14Q ). This strain phenocopies a wc-1 blind mutant and shows a strong reduction of light-induced transcriptional activation of both al-3 and vivid (vvd), another light-inducible gene. We mutated Neurospora GCN Five (ngf-1), which encodes a homologue of the yeast HAT Gcn5p, to generate a strain impaired in H3 K14 acetylation and found that it was defective in photoinduction. Together, our findings reveal a direct link between histone modification and light signaling in Neurospora and contribute to the developing understanding of the molecular mechanisms operating in light-inducible gene activation.

Background: Plasticity-related gene 5 (PRG5) is prominently expressed in neurons, but its neuronal function is unknown. Results: PRG5 overexpression prematurely induces spine-like structures in immature hippocampal neurons, and PRG5 knockdown causes functionally relevant loss of excitatory synapses in dendrites of more mature neurons. Conclusion: PRG5 expression is involved in proper spine formation. Significance: We describe a new function of PRG5 in spinogenesis.

Emerging epidemiology studies indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as viral or bacterial infections during pregnancy serves as a risk factor for multiple neurodevelopmental disorders including autism spectrum disorders and schizophrenia. Although alterations in the cortex and hippocampus of MIA offspring have been described, less evidence exists on the impact on the cerebellum. Here, we report altered expression of cytokines and chemokines in the cerebellum of MIA offspring, including increase in the neuroinflammatory cytokine TNFα and its receptor TNFR1. We also report reduced expression of the synaptic organizing proteins cerebellin-1 and GluRδ2. These synaptic protein alterations are associated with a deficit in the ability of cerebellar neurons to form synapses and an increased number of dendritic spines that are not in contact with a presynaptic terminal. These impairments are likely contributing to the behavioral deficits in the MIA exposed offspring.

Both genetic and environmental factors are thought to contribute to neurodevelopmental and neuropsychiatric disorders with maternal immune activation (MIA) being a risk factor for both autism spectrum disorders and schizophrenia. Although MIA mouse offspring exhibit behavioral impairments, the synaptic alterations in vivo that mediate these behaviors are not known. Here we employed in vivo multiphoton imaging to determine that in the cortex of young MIA offspring there is a reduction in number and turnover rates of dendritic spines, sites of majority of excitatory synaptic inputs. Significantly, spine impairments persisted into adulthood and correlated with increased repetitive behavior, an ASD relevant behavioral phenotype. Structural analysis of synaptic inputs revealed a reorganization of presynaptic inputs with a larger proportion of spines being contacted by both excitatory and inhibitory presynaptic terminals. These structural impairments were accompanied by altered excitatory and inhibitory synaptic transmission. Finally, we report that a postnatal treatment of MIA offspring with the anti-inflammatory drug ibudilast, prevented both synaptic and behavioral impairments. Our results suggest that a possible altered inflammatory state associated with maternal immune activation results in impaired synaptic development that persists into adulthood but which can be prevented with early anti-inflammatory treatment.

Recent and rapidly developing movements relating to the increasing awareness and reports of gender bias, discrimination, and abuse have reached the academic environments. The consideration that negative attitudes toward women and abuse of power creates a hostile environment for female scientists, facilitating sexual harassment and driving women out of science, can be easily related to. Rationally inaccessible gender biases are not only evident at the level of the researchers, but are also paralleled by a corresponding imbalance at the level of the research subjects. Here, we focus on the maternal immune activation (MIA) animal model to illustrate exemplarily the current state of ex-/inclusion of female research subjects and the consideration of sex as biological variable in the basic neurosciences. We demonstrate a strong sex disparity with a major emphasis on male animals in studies examining behavioral and neurochemical alterations in MIA offspring. We put forward the hypothesis that this neglect of female subjects in basic research may stem from a hard-wired sex/gender bias, which may also be reflected in a similar attitude toward female scientists. We suggest exploring the possibility that by dismantling sex bias and male dominance in basic research one would get an additional handle on favorably modifying the perception and appreciation for women in science.

Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500G > A (p.R167Q) mutation with~5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology. Hmbs knock-in mice (KI mice) model the rare homozygous dominant form of AIP and were used as tool to elucidate the hitherto unknown pathophysiology of the behavioral manifestations of the disease and its neural underpinnings. Extensive behavioral analyses revealed a selective depression-like phenotype in Hmbs KI mice; transcriptomic and immunohistochemical analyses demonstrated aberrant myelination. The uncovered compromised mitochondrial function in the hippocampus of knock-in mice and its ensuing neurogenic and neuroplastic deficits lead us to propose a mechanistic role for disrupted mitochondrial energy production in the pathogenesis of the behavioral consequences of severe HMBS deficiency and its neuropathological sequelae in the brain.

Plasticity-related gene 1 (PRG-1) is a novel player in glutamatergic synaptic transmission, acting by interfering with lysophosphatidic acid (LPA)-dependent signaling pathways. In the central nervous system, PRG-1 expression is restricted to postsynaptic dendrites on glutamatergic neurons. In this study, we describe the promoter architecture of the PRG-1 gene using RNA ligase-mediated rapid amplification of cDNA ends (RLM-Race) and PCR analysis. We found that PRG-1 expression is under the control of a TATA-less promoter with multiple transcription start sites. We demonstrated also that 200-kb genomic environment of the PRG-1 gene is sufficient to mediate cell type-specific expression in a reporter mouse model. Characterization of the PRG-1 promoter resulted in the identification of a 450-bp sequence, mediating ≈40-fold enhancement of transcription in cultured primary neurons compared to controls, and which induced reporter expression in slice cultures in neurons. Recently, the regulation of PRG-1 by the basic helix-loop-helix transcription factor Nex1 (Math2, NeuroD6) was reported. However, our studies in Nex1-null-mice revealed that Nex1-deficiency induces no change in PRG-1 expression and localization. We detected an additional Nex1-independent regulation mechanism that increases PRG-1 expression and mediates neuron-specific expression in an organotypic environment.