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Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment.
Muller CL, Anacker AM, Rogers TD, Goeden N, Keller EH, Forsberg CG, Kerr TM, Wender C, Anderson GM, Stanwood GD, Blakely RD, Bonnin A, Veenstra-VanderWeele J
(2017) Neuropsychopharmacology 42: 427-436
MeSH Terms: Animals, Female, Genotype, Maternal-Fetal Exchange, Mice, Inbred Strains, Mice, Transgenic, Placenta, Pregnancy, Prosencephalon, Rhombencephalon, Serotonin, Serotonin Plasma Membrane Transport Proteins, Thalamus
Show Abstract · Added August 31, 2018
Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo. We therefore used different combinations of maternal and embryo SERT Ala56 genotypes to examine effects on blood, placenta and embryo serotonin levels and neurodevelopment at embryonic day E14.5, when peripheral sources of 5-HT predominate, and E18.5, when midbrain 5-HT projections have reached the forebrain. Maternal SERT Ala56 genotype was associated with decreased placenta and embryonic forebrain 5-HT levels at E14.5. Low 5-HT in the placenta persisted, but forebrain levels normalized by E18.5. Maternal SERT Ala56 genotype effects on forebrain 5-HT levels were accompanied by a broadening of 5-HT-sensitive thalamocortical axon projections. In contrast, no effect of embryo genotype was seen in concepti from heterozygous dams. Blood 5-HT levels were dynamic across pregnancy and were increased in SERT Ala56 dams at E14.5. Placenta RNA sequencing data at E14.5 indicated substantial impact of maternal SERT Ala56 genotype, with alterations in immune and metabolic-related pathways. Collectively, these findings indicate that maternal SERT function impacts offspring placental 5-HT levels, forebrain 5-HT levels, and neurodevelopment.
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Differential impact of genetically modulated choline transporter expression on the release of endogenous versus newly synthesized acetylcholine.
Iwamoto H, Calcutt MW, Blakely RD
(2016) Neurochem Int 98: 138-45
MeSH Terms: Acetylcholine, Animals, Animals, Genetically Modified, Choline, Gene Expression, Genotype, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Potassium, Prosencephalon, Synaptic Transmission
Show Abstract · Added February 3, 2017
The efficient import of choline into cholinergic nerve terminals by the presynaptic, high-affinity choline transporter (CHT, SLC5A7) dictates the capacity for acetylcholine (ACh) synthesis and release. Tissue levels of ACh are significantly reduced in mice heterozygous for a loss of function mutation in Slc5a7 (HET, CHT(+/-)), but significantly elevated in overexpressing, Slc5a7 BAC-transgenic mice (BAC). Since the readily-releasable pool of ACh is thought to constitute a small fraction of the total ACh pool, these genotype-dependent changes raised the question as to whether CHT expression or activity might preferentially influence the size of reserve pool ACh vesicles. In the current study, we approached this question by evaluating CHT genotype effects on the release of ACh from suprafused mouse forebrain slices. We treated slices from HET, BAC or wildtype (WT) controls with elevated K(+) and monitored release of both newly synthesized and storage pools of ACh. Newly synthesized ACh produced following uptake of [(3)H]choline was quantified by scintillation spectrometry whereas release of endogenous ACh storage pools was quantified by an HPLC-MS approach, from the same samples. Whereas endogenous ACh release scaled with CHT gene dosage, preloaded [(3)H]ACh release displayed no significant genotype dependence. Our findings suggest that CHT protein levels preferentially impact the capacity for ACh release afforded by mobilization of reserve pool vesicles.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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Functional Connectome Analysis of Dopamine Neuron Glutamatergic Connections in Forebrain Regions.
Mingote S, Chuhma N, Kusnoor SV, Field B, Deutch AY, Rayport S
(2015) J Neurosci 35: 16259-71
MeSH Terms: Animals, Channelrhodopsins, DNA-Binding Proteins, Dopamine Plasma Membrane Transport Proteins, Dopaminergic Neurons, Excitatory Postsynaptic Potentials, Female, Glutamic Acid, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Neural Pathways, Neurotransmitter Agents, Phosphopyruvate Hydratase, Prosencephalon, Transduction, Genetic, Tyrosine 3-Monooxygenase, Ventral Tegmental Area
Show Abstract · Added February 22, 2016
UNLABELLED - In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome.
SIGNIFICANCE STATEMENT - Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain dopamine neurons are capable of glutamate cotransmission. With conditional expression of channelrhodopsin in dopamine neurons, we systematically explored dopamine neuron connections in the forebrain and identified regionally specific dopamine neuron excitatory connections. Establishing that only a subset of forebrain regions receive excitatory connections from dopamine neurons will help to determine the function of dopamine neuron glutamate cotransmission, which likely involves transmission of precise temporal signals and enhancement of the dynamic range of dopamine neuron signals.
Copyright © 2015 the authors 0270-6474/15/3516259-13$15.00/0.
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20 MeSH Terms
Transcriptional maturation of the mouse auditory forebrain.
Hackett TA, Guo Y, Clause A, Hackett NJ, Garbett K, Zhang P, Polley DB, Mirnics K
(2015) BMC Genomics 16: 606
MeSH Terms: Animals, Animals, Newborn, Auditory Cortex, Cluster Analysis, Databases, Genetic, Female, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Male, Mice, Prosencephalon, Sequence Analysis, RNA
Show Abstract · Added February 22, 2016
BACKGROUND - The maturation of the brain involves the coordinated expression of thousands of genes, proteins and regulatory elements over time. In sensory pathways, gene expression profiles are modified by age and sensory experience in a manner that differs between brain regions and cell types. In the auditory system of altricial animals, neuronal activity increases markedly after the opening of the ear canals, initiating events that culminate in the maturation of auditory circuitry in the brain. This window provides a unique opportunity to study how gene expression patterns are modified by the onset of sensory experience through maturity. As a tool for capturing these features, next-generation sequencing of total RNA (RNAseq) has tremendous utility, because the entire transcriptome can be screened to index expression of any gene. To date, whole transcriptome profiles have not been generated for any central auditory structure in any species at any age. In the present study, RNAseq was used to profile two regions of the mouse auditory forebrain (A1, primary auditory cortex; MG, medial geniculate) at key stages of postnatal development (P7, P14, P21, adult) before and after the onset of hearing (~P12). Hierarchical clustering, differential expression, and functional geneset enrichment analyses (GSEA) were used to profile the expression patterns of all genes. Selected genesets related to neurotransmission, developmental plasticity, critical periods and brain structure were highlighted. An accessible repository of the entire dataset was also constructed that permits extraction and screening of all data from the global through single-gene levels. To our knowledge, this is the first whole transcriptome sequencing study of the forebrain of any mammalian sensory system. Although the data are most relevant for the auditory system, they are generally applicable to forebrain structures in the visual and somatosensory systems, as well.
RESULTS - The main findings were: (1) Global gene expression patterns were tightly clustered by postnatal age and brain region; (2) comparing A1 and MG, the total numbers of differentially expressed genes were comparable from P7 to P21, then dropped to nearly half by adulthood; (3) comparing successive age groups, the greatest numbers of differentially expressed genes were found between P7 and P14 in both regions, followed by a steady decline in numbers with age; (4) maturational trajectories in expression levels varied at the single gene level (increasing, decreasing, static, other); (5) between regions, the profiles of single genes were often asymmetric; (6) GSEA revealed that genesets related to neural activity and plasticity were typically upregulated from P7 to adult, while those related to structure tended to be downregulated; (7) GSEA and pathways analysis of selected functional networks were not predictive of expression patterns in the auditory forebrain for all genes, reflecting regional specificity at the single gene level.
CONCLUSIONS - Gene expression in the auditory forebrain during postnatal development is in constant flux and becomes increasingly stable with age. Maturational changes are evident at the global through single gene levels. Transcriptome profiles in A1 and MG are distinct at all ages, and differ from other brain regions. The database generated by this study provides a rich foundation for the identification of novel developmental biomarkers, functional gene pathways, and targeted studies of postnatal maturation in the auditory forebrain.
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Quantitative proteomics analysis of CaMKII phosphorylation and the CaMKII interactome in the mouse forebrain.
Baucum AJ, Shonesy BC, Rose KL, Colbran RJ
(2015) ACS Chem Neurosci 6: 615-31
MeSH Terms: Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Membrane, Cytosol, Gene Knock-In Techniques, HEK293 Cells, Holoenzymes, Humans, Immunoprecipitation, Male, Mass Spectrometry, Mice, Transgenic, Phosphorylation, Prosencephalon, Proteomics, Recombinant Proteins, Sf9 Cells, Spodoptera, Synapses
Show Abstract · Added February 15, 2016
Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) autophosphorylation at Thr286 and Thr305/Thr306 regulates kinase activity and modulates subcellular targeting and is critical for normal synaptic plasticity and learning and memory. Here, a mass spectrometry-based approach was used to identify Ca(2+)-dependent and -independent in vitro autophosphorylation sites in recombinant CaMKIIα and CaMKIIβ. CaMKII holoenzymes were then immunoprecipitated from subcellular fractions of forebrains isolated from either wild-type (WT) mice or mice with a Thr286 to Ala knock-in mutation of CaMKIIα (T286A-KI mice) and analyzed using the same approach in order to characterize in vivo phosphorylation sites in both CaMKII isoforms and identify CaMKII-associated proteins (CaMKAPs). A total of six and seven autophosphorylation sites in CaMKIIα and CaMKIIβ, respectively, were detected in WT mice. Thr286-phosphorylated CaMKIIα and Thr287-phosphorylated CaMKIIβ were selectively enriched in WT Triton-insoluble (synaptic) fractions compared to Triton-soluble (membrane) and cytosolic fractions. In contrast, Thr306-phosphorylated CaMKIIα and Ser315- and Thr320/Thr321-phosphorylated CaMKIIβ were selectively enriched in WT cytosolic fractions. The T286A-KI mutation significantly reduced levels of phosphorylation of CaMKIIα at Ser275 across all subcellular fractions and of cytosolic CaMKIIβ at Ser315 and Thr320/Thr321. Significantly more CaMKAPs coprecipitated with WT CaMKII holoenzymes in the synaptic fraction compared to that in the membrane fraction, with functions including scaffolding, microtubule organization, actin organization, ribosomal function, vesicle trafficking, and others. The T286A-KI mutation altered the interactions of multiple CaMKAPs with CaMKII, including several proteins linked to autism spectrum disorders. These data identify CaMKII isoform phosphorylation sites and a network of synaptic protein interactions that are sensitive to the abrogation of Thr286 autophosphorylation of CaMKIIα, likely contributing to the diverse synaptic and behavioral deficits of T286A-KI mice.
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19 MeSH Terms
Identification and characterization of ML352: a novel, noncompetitive inhibitor of the presynaptic choline transporter.
Ennis EA, Wright J, Retzlaff CL, McManus OB, Lin Z, Huang X, Wu M, Li M, Daniels JS, Lindsley CW, Hopkins CR, Blakely RD
(2015) ACS Chem Neurosci 6: 417-27
MeSH Terms: Animals, Benzamides, Choline, Dose-Response Relationship, Drug, Enzyme Inhibitors, Gene Expression Regulation, HEK293 Cells, Hemicholinium 3, Humans, Isoxazoles, Male, Membrane Potentials, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Models, Biological, Mutation, Neural Inhibition, Prosencephalon, Protein Binding, Rats, Rats, Sprague-Dawley, Synaptosomes
Show Abstract · Added February 12, 2015
The high-affinity choline transporter (CHT) is the rate-limiting determinant of acetylcholine (ACh) synthesis, yet the transporter remains a largely undeveloped target for the detection and manipulation of synaptic cholinergic signaling. To expand CHT pharmacology, we pursued a high-throughput screen for novel CHT-targeted small molecules based on the electrogenic properties of transporter-mediated choline transport. In this effort, we identified five novel, structural classes of CHT-specific inhibitors. Chemical diversification and functional analysis of one of these classes identified ML352 as a high-affinity (Ki = 92 nM) and selective CHT inhibitor. At concentrations that fully antagonized CHT in transfected cells and nerve terminal preparations, ML352 exhibited no inhibition of acetylcholinesterase (AChE) or cholineacetyltransferase (ChAT) and also lacked activity at dopamine, serotonin, and norepinephrine transporters, as well as many receptors and ion channels. ML352 exhibited noncompetitive choline uptake inhibition in intact cells and synaptosomes and reduced the apparent density of hemicholinium-3 (HC-3) binding sites in membrane assays, suggesting allosteric transporter interactions. Pharmacokinetic studies revealed limited in vitro metabolism and significant CNS penetration, with features predicting rapid clearance. ML352 represents a novel, potent, and specific tool for the manipulation of CHT, providing a possible platform for the development of cholinergic imaging and therapeutic agents.
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23 MeSH Terms
Absence of Ca2+-stimulated adenylyl cyclases leads to reduced synaptic plasticity and impaired experience-dependent fear memory.
Wieczorek L, Majumdar D, Wills TA, Hu L, Winder DG, Webb DJ, Muglia LJ
(2012) Transl Psychiatry 2: e126
MeSH Terms: Adenylyl Cyclases, Animals, Calcium, Crosses, Genetic, Fear, Gene-Environment Interaction, Hippocampus, Long-Term Potentiation, Membrane Glycoproteins, Mental Recall, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins, Neurogenesis, Neuronal Plasticity, Prosencephalon, Synapses
Show Abstract · Added May 19, 2014
Ca(2+)-stimulated adenylyl cyclase (AC) 1 and 8 are two genes that have been shown to play critical roles in fear memory. AC1 and AC8 couple neuronal activity and intracellular Ca(2+) increases to the production of cyclic adenosine monophosphate and are localized synaptically, suggesting that Ca(2+)-stimulated ACs may modulate synaptic plasticity. Here, we first established that Ca(2+)-stimulated ACs modulate protein markers of synaptic activity at baseline and after learning. Primary hippocampal cell cultures showed that AC1/AC8 double-knockout (DKO) mice have reduced SV2, a synaptic vesicle protein, abundance along their dendritic processes, and this reduction can be rescued through lentivirus delivery of AC8 to the DKO cells. Additionally, phospho-synapsin, a protein implicated in the regulation of neurotransmitter release at the synapse, is decreased in vivo 1 h after conditioned fear (CF) training in DKO mice. Importantly, additional experiments showed that long-term potentiation deficits present in DKO mice are rescued by acutely replacing AC8 in the forebrain, further supporting the idea that Ca(2+)-stimulated AC activity is a crucial modulator of synaptic plasticity. Previous studies have demonstrated that memory is continually modulated by gene-environment interactions. The last set of experiments evaluated the effects of knocking out AC1 and AC8 genes on experience-dependent changes in CF memory. We showed that the strength of CF memory in wild-type mice is determined by previous environment, minimal or enriched, whereas memory in DKO mice is unaffected. Thus, overall these results show that AC1 and AC8 modulate markers of synaptic activity and help integrate environmental information to modulate fear memory.
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18 MeSH Terms
Substrate-selective and calcium-independent activation of CaMKII by α-actinin.
Jalan-Sakrikar N, Bartlett RK, Baucum AJ, Colbran RJ
(2012) J Biol Chem 287: 15275-83
MeSH Terms: Actinin, Actins, Amino Acid Sequence, Animals, Binding Sites, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Enzyme Activation, HEK293 Cells, Humans, Immunoblotting, Mice, Microscopy, Fluorescence, Models, Molecular, Molecular Sequence Data, Mutation, Phosphorylation, Prosencephalon, Protein Binding, Protein Structure, Tertiary, Receptors, N-Methyl-D-Aspartate, Sequence Homology, Amino Acid, Serine, Substrate Specificity, Threonine
Show Abstract · Added December 5, 2013
Protein-protein interactions are thought to modulate the efficiency and specificity of Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) signaling in specific subcellular compartments. Here we show that the F-actin-binding protein α-actinin targets CaMKIIα to F-actin in cells by binding to the CaMKII regulatory domain, mimicking CaM. The interaction with α-actinin is blocked by CaMKII autophosphorylation at Thr-306, but not by autophosphorylation at Thr-305, whereas autophosphorylation at either site blocks Ca(2+)/CaM binding. The binding of α-actinin to CaMKII is Ca(2+)-independent and activates the phosphorylation of a subset of substrates in vitro. In intact cells, α-actinin selectively stabilizes CaMKII association with GluN2B-containing glutamate receptors and enhances phosphorylation of Ser-1303 in GluN2B, but inhibits CaMKII phosphorylation of Ser-831 in glutamate receptor GluA1 subunits by competing for activation by Ca(2+)/CaM. These data show that Ca(2+)-independent binding of α-actinin to CaMKII differentially modulates the phosphorylation of physiological targets that play key roles in long-term synaptic plasticity.
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25 MeSH Terms
A transient placental source of serotonin for the fetal forebrain.
Bonnin A, Goeden N, Chen K, Wilson ML, King J, Shih JC, Blakely RD, Deneris ES, Levitt P
(2011) Nature 472: 347-50
MeSH Terms: Animals, Embryo, Mammalian, Female, Fetus, Humans, In Vitro Techniques, Maternal-Fetal Exchange, Mice, Placenta, Pregnancy, Prenatal Exposure Delayed Effects, Prosencephalon, Raphe Nuclei, Rhombencephalon, Serotonin, Time Factors, Transcription Factors
Show Abstract · Added July 10, 2013
Serotonin (5-hydroxytryptamine or 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. It is thought that beyond fetal 5-HT neurons there are significant maternal contributions to fetal 5-HT during pregnancy but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used Pet1(-/-) (also called Fev) mice in which most dorsal raphe neurons lack 5-HT. We detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source. We uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and indicates that maternal-placental-fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.
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Homologs of genes expressed in Caenorhabditis elegans GABAergic neurons are also found in the developing mouse forebrain.
Hammock EA, Eagleson KL, Barlow S, Earls LR, Miller DM, Levitt P
(2010) Neural Dev 5: 32
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cell Separation, Chromosome Mapping, Flow Cytometry, Gene Expression Profiling, Humans, In Situ Hybridization, Mice, Mice, Inbred C57BL, Neurogenesis, Neurons, Prosencephalon, Sequence Homology, Amino Acid, gamma-Aminobutyric Acid
Show Abstract · Added February 3, 2014
BACKGROUND - In an effort to identify genes that specify the mammalian forebrain, we used a comparative approach to identify mouse homologs of transcription factors expressed in developing Caenorhabditis elegans GABAergic neurons. A cell-specific microarray profiling study revealed a set of transcription factors that are highly expressed in embryonic C. elegans GABAergic neurons.
RESULTS - Bioinformatic analyses identified mouse protein homologs of these selected transcripts and their expression pattern was mapped in the mouse embryonic forebrain by in situ hybridization. A review of human homologs indicates several of these genes are potential candidates in neurodevelopmental disorders.
CONCLUSIONS - Our comparative approach has revealed several novel candidates that may serve as future targets for studies of mammalian forebrain development.
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16 MeSH Terms