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Activity‐regulated cytoskeleton‐associated protein (Arc) is an immediate early gene product that support neuroplastic changes important for cognitive function and memory formation. As a protein with homology to the retroviral Gag protein, a particular characteristic of Arc is its capacity to self‐assemble into virus‐like capsids that can package mRNAs and transfer those transcripts to other cells. Although a lot has been uncovered about the contributions of Arc to neuron biology and behavior, very little is known about how different functions of Arc are coordinately regulated both temporally and spatially in neurons. The answer to this question we hypothesized must involve the occurrence of different protein post‐translational modifications acting to confer specificity. In this study, we used mass spectrometry and sequence prediction strategies to map novel Arc phosphorylation sites. Our approach led us to recognize serine 67 (S67) and threonine 278 (T278) as residues that can be modified by TNIK, which is a kinase abundantly expressed in neurons that shares many functional overlaps with Arc and has, along with its interacting proteins such as the NMDA receptor, and been implicated as a risk factor for psychiatric disorders. Furthermore, characterization of each residue using site‐directed mutagenesis to create S67 and T278 mutant variants revealed that TNIK action at those amino acids can strongly influence Arc's subcellular distribution and self‐assembly as capsids. Together, our findings reveal an unsuspected connection between Arc and TNIK. Better understanding of the interplay between these two proteins in neuronal cells could lead to new insights about apparition and progression of psychiatric disorders. Cover Image for this issue: https://doi.org/10.1111/jnc.15077 [ABSTRACT FROM AUTHOR]

The role of Arc in synaptic plasticity and memory consolidation has been investigated for many years with recent evidence that defects in the expression or activity of this immediateearly gene may also contribute to the pathophysiology of brain disorders including schizophrenia and fragile X syndrome. These results bring forward the concept that reversing Arc abnormalities could provide an avenue to improve cognitive or neurological impairments in different disease contexts, but how to achieve this therapeutic objective has remained elusive. Here, we present results from a chemogenomic screen that probed a mechanistically diverse library of small molecules for modulators of BDNF-induced Arc expression in primary cortical neurons. This effort identified compounds with a range of influences on Arc, including promoting its acetylation--a previously uncharacterized post-translational modification of this protein. Together, our data provide insights into the control of Arc that could be targeted to harness neuroplasticity for clinical applications. [ABSTRACT FROM AUTHOR]

Although circular RNAs (circRNAs) are enriched in the brain, their relevance for brain function and psychiatric disorders is poorly understood. Here, we show that circHomer1 is inversely associated with relative HOMER1B mRNA isoform levels in both the orbitofrontal cortex (OFC) and stem-cell-derived neuronal cultures of subjects with psychiatric disorders. We further demonstrate that in vivo circHomer1 knockdown (KD) within the OFC can inhibit the synaptic expression of Homer1b mRNA. Furthermore, we show that circHomer1 directly binds to Homer1b mRNA and that Homer1b -specific KD increases synaptic circHomer1 levels and improves OFC-mediated behavioral flexibility. Importantly, double circHomer1 and Homer1b in vivo co-KD results in a complete rescue in circHomer1 -associated alterations in both chance reversal learning and synaptic gene expression. Lastly, we uncover an RNA-binding protein that can directly bind to circHomer1 and promote its biogenesis. Taken together, our data provide mechanistic insights into the importance of circRNAs in brain function and disease. [Display omitted] • Expression of c ircHomer1 is inversely associated with relative HOMER1B mRNA levels • CircHomer1 and Homer1b bind to each other and inhibit each other's synaptic expression • In vivo KD of Homer1b improves OFC-mediated chance reversal learning • Co-KD of Homer1b and circHomer1 restores chance reversal learning Through in vivo circRNA and mRNA isoform-specific knockdown in mouse orbitofrontal cortex (OFC), Hafez et al. elucidate the antagonistic interaction between the psychiatric-disease-associated circHomer1 and Homer1b mRNA and their opposing effects on OFC-mediated reversal learning. [ABSTRACT FROM AUTHOR]

Elevation of intracellular Ca&sup2+; levels activates calcium/calmodulin-dependent protein kinase (CaMK) IV, which in turn plays an important role in neuroprotection and neuroplasticity. The possibility that CaMKIV is similarly involved in neocortical tissue has not been examined previously, especially with regard to the plastic nature of ocular dominance features in the primary visual cortex (area V1). We addressed this question by way of monocular enucleation (ME) to disrupt sensory input and examine CaMKIV expression changes in monkey area V1. Immunohistochemical staining of area V1 in normal infants showed a nuclear presence of CaMKIV, which did not changed after ME. However, a striking set of layer- and time-dependent changes in nuclear CaMKIV expression was observed in adult area V1 after ME. A strong increase in nuclear CaMKIV levels was evident in cortical layers II/III and VI after 1 d of ME and in layer IVC after 5 d of ME. These specific laminar changes persisted after 30 d of ME and, most notably, showed a columnar profile in which CaMKIV expression was linked to open-eye columns. Real-time quantitative reverse transcription-PCR and Western blot analysis showed that total amounts of CaMKIV mRNA and protein remained unchanged after ME, suggesting that a nuclear translocation may occur from the cytoplasm. Finally, double-label immunohistochemical staining with a pyramidal cell marker (SMI-32) showed that CaMKIV was absent in this subtype, whereas coincidental expression with GABA, parvalbumin, and calretinin, but not calbindin, showed its clear presence in a subset of interneurons. We propose that CaMKIV activity within diverse groups of cortical interneurons may play an important role in adaptive plastic reorganization of adult neocortical tissue. [ABSTRACT FROM AUTHOR]

Discrimination thresholds were obtained using a delayed spatial frequency discrimination task. In Experiment 1, we found that presentation of a mask 3 s before onset of a reference Gabor patch caused a selective, spatial frequency dependent interference in a subsequent discrimination task. However, a 10 s interval abolished this masking effect. In Experiment 2, the mask was associated with a second spatial frequency discrimination task so that a representation of the mask had to be coded into short-term perceptual memory. This experiment was performed to assess whether absence of masking in the 10 s condition of Experiment 1 might be due to decay of the mask information in the perceptual or the memory representational domain. The presence of this second discrimination task now caused similar interference effects on the primary discrimination task at both the 3 s and 10 s interstimulus intervals (ISI) conditions. Finally, to test the robustness of the masking effect, the nature of the secondary masking task was changed from a spatial frequency discrimination task to an orientation discrimination task in Experiment 3. The masking effect was now abolished in both the 3 and 10 s ISI conditions. Together, the results from these experiments are consistent with the idea of a two-level perceptual memory mechanism. The results also suggest that stimulus representations during a perceptual discrimination task are shared between the perceptual and memory representation domains in a task-dependent manner. [Copyright &y& Elsevier]

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a heritable neuropsychiatric disorder with largely unknown pathogenesis. Given their prominent role in brain function and disease, we hypothesized that microRNAs (miRNAs) might be of importance for BD. Here we show that levels of miR-34a, which is predicted to target multiple genes implicated as genetic risk factors for BD, are increased in postmortem cerebellar tissue from BD patients, as well as in BD patient-derived neuronal cultures generated by reprogramming of human fibroblasts into induced neurons (iNs) or into induced pluripotent stem cells (iPSCs) subsequently differentiated into neurons. Of the predicted miR-34a targets, we validated the BD risk genes ankyrin-3 (ANK3) and voltage-dependent L-type calcium channel subunit beta-3 (CACNB3) as direct miR-34a targets. Using human iPSC-derived neuronal progenitor cells (hNPCs), we further show that enhancement of miR-34a expression impairs neuronal differentiation, expression of synaptic proteins and neuronal morphology, whereas reducing endogenous miR-34a expression enhances dendritic elaboration. Taken together, we propose that miR-34a serves as a critical link between multiple etiological factors for BD and its pathogenesis through the regulation of a molecular network essential for neuronal development and synaptogenesis.