Expression of the primate-specific LINC00473 RNA in mouse neurons promotes excitability and CREB-regulated transcription.

The LINC00473 (Lnc473) gene has previously been shown to be associated with cancer and psychiatric disorders. Its expression is elevated in several types of tumors and decreased in the brains of patients diagnosed with schizophrenia or major depression. In neurons, Lnc473 transcription is strongly responsive to synaptic activity, suggesting a role in adaptive, plasticity-related mechanisms.

N-methyl-d-aspartate Receptor-mediated Preconditioning Mitigates Excitotoxicity in Human Induced Pluripotent Stem Cell-derived Brain Organoids.

Studies in rodent models of acute and chronic neurodegenerative disorders have uncovered that glutamate-induced excitotoxic cell death is mediated primarily by extrasynaptic N-methyl-d-aspartate receptors (NMDARs). Rodent neurons can also build up in an activity-dependent manner a protective shield against excitotoxicity. This form of acquired neuroprotection is induced by preconditioning with low doses of NMDA or by activation of synaptic NMDARs triggered by bursts of action potentials.

Npas4 regulates medium spiny neuron physiology and gates cocaine-induced hyperlocomotion.

We show here that the transcription factor Npas4 is an important regulator of medium spiny neuron spine density and electrophysiological parameters and that it determines the magnitude of cocaine-induced hyperlocomotion in mice. Npas4 is induced by synaptic stimuli that cause calcium influx, but not dopaminergic or PKA-stimulating input, in mouse medium spiny neurons and human iPSC-derived forebrain organoids. This induction is independent of ubiquitous kinase pathways such as PKA and MAPK cascades, and instead depends on calcineurin and nuclear calcium signalling.

Shaping the human brain: evolutionary cis-regulatory plasticity drives changes in synaptic activity-controlled adaptive gene expression.

Neuronal activity-induced gene expression programs involved in synaptic structure- and plasticity-related functions are similar in mice and humans, yet bear distinct features. These include gains or losses of activity-responsiveness of certain genes and differences in gene induction profiles. Here, we discuss a possible origin of dissimilarities in activity-regulated transcription between species.

Lineage divergence of activity-driven transcription and evolution of cognitive ability.

Excitation-transcription coupling shapes network formation during brain development and controls neuronal survival, synaptic function and cognitive skills in the adult. New studies have uncovered differences in the transcriptional responses to synaptic activity between humans and mice. These differences are caused both by the emergence of lineage-specific activity-regulated genes and by the acquisition of signal-responsive DNA elements in gene regulatory regions that determine whether a gene can be transcriptionally induced by synaptic activity or alter the extent of its inducibility.

The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A.

Transcription factor 4 (TCF4 also known as ITF2 or E2-2) is a basic helix-loop-helix (bHLH) protein associated with Pitt-Hopkins syndrome, intellectual disability, and schizophrenia (SCZ). Here, we show that TCF4-dependent transcription in cortical neurons cultured from embryonic rats of both sexes is induced by neuronal activity via soluble adenylyl cyclase and protein kinase A (PKA) signaling. PKA phosphorylates TCF4 directly and a PKA phosphorylation site in TCF4 is necessary for its transcriptional activity in cultured neurons and in the developing brain We also demonstrate that (growth arrest and DNA damage inducible gamma) is a direct target of neuronal-activity-induced, TCF4-dependent transcriptional regulation and that TCF4 missense variations identified in SCZ patients alter the transcriptional activity of TCF4 in neurons.

Ultrastructural Characterization of Zika Virus Replication Factories.

A global concern has emerged with the pandemic spread of Zika virus (ZIKV) infections that can cause severe neurological symptoms in adults and newborns. ZIKV is a positive-strand RNA virus replicating in virus-induced membranous replication factories (RFs). Here we used various imaging techniques to investigate the ultrastructural details of ZIKV RFs and their relationship with host cell organelles.

Networks of Cultured iPSC-Derived Neurons Reveal the Human Synaptic Activity-Regulated Adaptive Gene Program.

Long-term adaptive responses in the brain, such as learning and memory, require synaptic activity-regulated gene expression, which has been thoroughly investigated in rodents. Using human iPSC-derived neuronal networks, we show that the human and the mouse synaptic activity-induced transcriptional programs share many genes and both require Ca-regulated synapse-to-nucleus signaling. Species-specific differences include the noncoding RNA genes BRE-AS1 and LINC00473 and the protein-coding gene ZNF331, which are absent in the mouse genome, as well as several human genes whose orthologs are either not induced by activity or are induced with different kinetics in mice.

Regulation of different human NFAT isoforms by neuronal activity.

Nuclear factor of activated T-cells (NFAT) is a family of transcription factors comprising four calcium-regulated members: NFATc1, NFATc2, NFATc3, and NFATc4. Upon activation by the calcium-dependent phosphatase calcineurin (CaN), NFATs translocate from cytosol to the nucleus and regulate their target genes, which in the nervous system are involved in axon growth, synaptic plasticity, and neuronal survival. We have shown previously that there are a number of different splice variants of NFAT genes expressed in the brain.

AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop in Cortical Neurons.

Unlabelled: Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, regulates both survival and differentiation of several neuronal populations in the nervous system during development, as well as synaptic plasticity in the adult brain. BDNF exerts its biological functions through its receptor TrkB. Although the regulation of BDNF transcription by neuronal activity has been widely studied, little is known about TrkB signaling-dependent expression of BDNF.

GLI2 cell-specific activity is controlled at the level of transcription and RNA processing: Consequences to cancer metastasis.

High activity of GLI family zinc finger protein 2 (GLI2) promotes tumor progression. Removal of the repressor domain at the N terminus (GLI2∆N) by recombinant methods converts GLI2 into a powerful transcriptional activator. However, molecular mechanisms leading to the formation of GLI2∆N activator proteins have not been established.

Subcellular localization and transcription regulatory potency of KCNIP/Calsenilin/DREAM/KChIP proteins in cultured primary cortical neurons do not provide support for their role in CRE-dependent gene expression.

KCNIP3/KChIP3 (voltage-dependent K+ channel interacting protein 3), alias Calsenilin and downstream regulatory element antagonist modulator (DREAM), is a multifunctional protein that modulates A-type potassium channels, affects processing of amyloid precursor protein and regulates transcription. KCNIP3 has been described to negatively influence the activity of CREB (cAMP/Ca(2+)-response element binding protein), an essential factor in neuronal activity-dependent gene expression regulation. However, reports on intracellular localization of KCNIP3 in neurons are diverse and necessitate additional analyses of distribution of KCNIPs in cells to clarify the potential of KCNIP3 to fulfill its functions in different cell compartments.

Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.

Transcription factor TCF4 (alias ITF2, SEF2 or E2-2) is a broadly expressed basic helix-loop-helix (bHLH) protein that functions as a homo- or heterodimer. Missense, nonsense, frame-shift and splice-site mutations as well as translocations and large deletions encompassing TCF4 gene cause Pitt-Hopkins syndrome (PTHS), a rare developmental disorder characterized by severe motor and mental retardation, typical facial features and breathing anomalies. Irrespective of the mutation, TCF4 haploinsufficiency has been proposed as an underlying mechanism for PTHS.

Bidirectional transcription from human LRRTM2/CTNNA1 and LRRTM1/CTNNA2 gene loci leads to expression of N-terminally truncated CTNNA1 and CTNNA2 isoforms.

α-Catenins (CTNNAs) are essential for the regulation of cell-cell and cell-matrix interactions in tissues. All human CTNNA genes contain antisense oriented leucine rich repeat transmembrane (LRRTM) genes within their seventh introns. Recently, a haplotype upstream of one of the human LRRTM genes, LRRTM1 that resides in CTNNA2, was shown to be associated with handedness and schizophrenia.

Identification of cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene.

Brain-derived neurotrophic factor (BDNF) is an important mediator of activity-dependent functions of the nervous system and its expression is dysregulated in several neuropsychiatric disorders. Regulation of rodent BDNF neuronal activity-dependent transcription has been relatively well characterized. Here, we have studied regulation of human BDNF (hBDNF) transcription by membrane depolarization of cultured mouse or rat primary cortical neurons expressing hBDNF gene or transfected with hBDNF promoter constructs, respectively.

Nuclear factor of activated T-cells isoform c4 (NFATc4/NFAT3) as a mediator of antiapoptotic transcription in NMDA receptor-stimulated cortical neurons.

During cortical development, when NR2B subunit is the major component of the NMDA glutamate receptors (NMDARs), moderate NMDAR activity supports neuronal survival at least in part by regulating gene transcription. We report that, in cultured cortical neurons from newborn rats, the NMDARs activated the calcium-responsive transcription regulator nuclear factor of activated T cells (NFAT). Moreover, in developing rat cortex, the NFAT isoforms c3 and c4 (NFATc3 and NFATc4) were expressed at relatively higher levels at postnatal day 7 (P7) than P21, overlapping with the period of NMDAR-dependent survival.

NF-kappaB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein.

X chromosome-linked inhibitor of apoptosis protein (XIAP) is an anti-apoptotic protein enhancing cell survival. Brain-derived neurotrophic factor (BDNF) also promotes neuronal viability but the links between XIAP and BDNF have remained unclear. We show here that the overexpression of XIAP increases BDNF in transgenic mice and cultured rat hippocampal neurons, whereas downregulation of XIAP by silencing RNA decreased BDNF.

Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice.

Background: Brain-derived neurotrophic factor (BDNF) is a small secreted protein that has important roles in the developing and adult nervous system. Altered expression or changes in the regulation of the BDNF gene have been implicated in a variety of human nervous system disorders. Although regulation of the rodent BDNF gene has been extensively investigated, in vivo studies regarding the human BDNF gene are largely limited to postmortem analysis.

N-terminally truncated BAF57 isoforms contribute to the diversity of SWI/SNF complexes in neurons.

The SWItch/Sucrose NonFermentable, a nucleosome remodeling complex (SWI/SNF) chromatin-remodelling complexes act upon the nucleosomal structure and regulate transcription, replication, repair of chromatin and splicing. In this study, we present evidence that human, mouse and rat genes encoding one of the SWI/SNF complex subunits, BAF57, undergo neuron-specific splicing of exons II, III and IV. Alternative splicing yields in at least three isoforms of BAF57 protein that have truncated N-termini (N-BAF57s).

Long-lasting behavioural and molecular alterations induced by early postnatal fluoxetine exposure are restored by chronic fluoxetine treatment in adult mice.

There is evidence that antidepressant drug treatment during a critical period of postnatal development renders mice susceptible to depression- and anxiety-related behaviour in adulthood. The mechanism of how early antidepressant treatment brings about long-term effects in emotional behaviour is not yet understood, but neurotrophins, particularly brain-derived neurotrophic factor (BDNF), have been implicated in this context. We examined the long-term effects of a transient early postnatal fluoxetine treatment on depression- and anxiety-related behaviours as well as gene expression of BDNF and its receptor TrkB in C57BL/6J mice.

Alternative splicing and expression of human and mouse NFAT genes.

Four members of the nuclear factor of activated T cells (NFAT) family (NFATC1, NFATC2, NFATC3, and NFATC4) are Ca(2+)-regulated transcription factors that regulate several processes in vertebrates, including the development and function of the immune, cardiovascular, musculoskeletal, and nervous systems. Here we describe the structures and alternative splicing of the human and mouse NFAT genes, including novel splice variants for NFATC1, NFATC2, NFATC3, and NFATC4, and show the expression of different NFAT mRNAs in various mouse and human tissues and brain regions by RT-PCR. Our results show that alternatively spliced NFAT mRNAs are expressed differentially and could contribute to the diversity of functions of the NFAT proteins.

A novel N-terminal isoform of the neuron-specific K-Cl cotransporter KCC2.

The neuronal K-Cl cotransporter KCC2 maintains the low intracellular chloride concentration required for the hyperpolarizing actions of inhibitory neurotransmitters gamma-aminobutyric acid and glycine in the central nervous system. This study shows that the mammalian KCC2 gene (alias Slc12a5) generates two neuron-specific isoforms by using alternative promoters and first exons. The novel KCC2a isoform differs from the only previously known KCC2 isoform (now termed KCC2b) by 40 unique N-terminal amino acid residues, including a putative Ste20-related proline alanine-rich kinase-binding site.

Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters.

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has central roles in the development, physiology, and pathology of the nervous system. We have elucidated the structure of the human BDNF gene, identified alternative transcripts, and studied their expression in adult human tissues and brain regions. In addition, the transcription initiation sites for human BDNF transcripts were determined and the activities of BDNF promoters were analyzed in transient overexpression assays.

Neuronal K+/Cl- co-transporter (KCC2) transgenes lacking neurone restrictive silencer element recapitulate CNS neurone-specific expression and developmental up-regulation of endogenous KCC2 gene.

The K+/Cl- co-transporter KCC2 maintains the low intracellular chloride concentration required for fast synaptic inhibition and is exclusively expressed in neurones of the CNS. Here, we show that the KCC2 gene (alias SLC12a5) has multiple transcription start sites and characterize the activity of 6.8 kb of mouse KCC2 gene regulatory sequence (spanning 1.

Structure, alternative splicing, and expression of the human and mouse KCNIP gene family.

Potassium channel-interacting proteins (KCNIPs, also named KChIPs) modulate A-type potassium channels and favor their surface expression. In addition, KCNIPs have been shown to interact with presenilins and also to function as transcriptional repressors. Here we describe the structures and alternative splicing of the human and mouse KCNIP genes, including novel splice variants for KCNIP1, KCNIP3, and KCNIP4, and show the expression of different KCNIP mRNAs in various mouse and human tissues and brain regions by RT-PCR.