@article {1468, title = {Neurotransmitter Switching Regulated by miRNAs Controls Changes in Social Preference.}, journal = {Neuron}, volume = {95}, year = {2017}, month = {2017 Sep 13}, pages = {1319-1333.e5}, abstract = {

Changes in social preference of amphibian larvae result from sustained exposure to kinship odorants. To understand the molecular and cellular mechanisms of this neuroplasticity, we investigated the effects of olfactory system activation on neurotransmitter (NT) expression in accessory olfactory bulb (AOB) interneurons during development. We show that protracted exposure to kin or non-kin odorants\ changes the number of dopamine (DA)- or gamma aminobutyric acid (GABA)-expressing neurons, with\ corresponding changes in attraction/aversion behavior. Changing the relative number of dopaminergic and GABAergic AOB interneurons or locally introducing DA or GABA receptor antagonists alters kinship preference. We then isolate AOB microRNAs (miRs) differentially regulated across these conditions. Inhibition of miR-375 and miR-200b reveals that they target Pax6 and Bcl11b to regulate the dopaminergic and GABAergic phenotypes. The results illuminate the role of NT switching governing experience-dependent social preference. VIDEO ABSTRACT.

}, keywords = {Animals, Choice Behavior, Dopamine, Dopamine Antagonists, GABA Antagonists, gamma-Aminobutyric Acid, Interneurons, MicroRNAs, Neurons, Neurotransmitter Agents, Olfactory Bulb, PAX6 Transcription Factor, Pheromones, Siblings, Social Behavior, Transcription Factors, Xenopus laevis, Xenopus Proteins}, issn = {1097-4199}, doi = {10.1016/j.neuron.2017.08.023}, author = {Dulcis, Davide and Lippi, Giordano and Stark, Christiana J and Do, Long H and Berg, Darwin K and Spitzer, Nicholas C} } @article {135, title = {cJun integrates calcium activity and tlx3 expression to regulate neurotransmitter specification.}, journal = {Nat Neurosci}, volume = {13}, year = {2010}, month = {2010 Aug}, pages = {944-50}, abstract = {

Neuronal differentiation is accomplished through cascades of intrinsic genetic factors initiated in neuronal progenitors by external gradients of morphogens. Activity has been thought to be important only late in development, but recent evidence suggests that activity also regulates early neuronal differentiation. Activity in post-mitotic neurons before synapse formation can regulate phenotypic specification, including neurotransmitter choice, but the mechanisms are not clear. We identified a mechanism that links endogenous calcium spike activity with an intrinsic genetic pathway to specify neurotransmitter choice in neurons in the dorsal embryonic spinal cord of Xenopus tropicalis. Early activity modulated transcription of the GABAergic/glutamatergic selection gene tlx3 through a variant cAMP response element (CRE) in its promoter. The cJun transcription factor bound to this CRE site, modulated transcription and regulated neurotransmitter phenotype via its transactivation domain. Calcium signaled through cJun N-terminal phosphorylation, which integrated activity-dependent and intrinsic neurotransmitter specification. This mechanism provides a basis for early activity to regulate genetic pathways at critical decision points, switching the phenotype of developing neurons.

}, keywords = {Animals, Base Sequence, Calcium, Calcium Signaling, Electrophoretic Mobility Shift Assay, Gene Expression, Gene Expression Regulation, Developmental, Homeodomain Proteins, Immunohistochemistry, In Situ Hybridization, Molecular Sequence Data, Neurogenesis, Neurons, Neurotransmitter Agents, Promoter Regions, Genetic, Proto-Oncogene Proteins c-jun, Response Elements, Reverse Transcriptase Polymerase Chain Reaction, Xenopus, Xenopus Proteins}, issn = {1546-1726}, doi = {10.1038/nn.2582}, author = {Marek, Kurt W and Kurtz, Lisa M and Spitzer, Nicholas C} } @article {134, title = {Target-dependent regulation of neurotransmitter specification and embryonic neuronal calcium spike activity.}, journal = {J Neurosci}, volume = {30}, year = {2010}, month = {2010 Apr 21}, pages = {5792-801}, abstract = {

Neurotransmitter specification has been shown to depend on genetic programs and electrical activity; however, target-dependent regulation also plays important roles in neuronal development. We have investigated the impact of muscle targets on transmitter specification in Xenopus spinal neurons using a neuron-muscle coculture system. We find that neuron-muscle contact reduces the number of neurons expressing the noncholinergic transmitters GABA, glycine, and glutamate, while having no effect on the incidence of ChAT expression. We show that muscle activity is necessary for target-dependent reduction of noncholinergic transmitter expression. In addition, we demonstrate that coculture with muscle cells suppresses early spontaneous calcium spike activity in neurons and the presence of muscle cells abolishes activity-dependent transmitter specification. The results indicate that target-dependent regulation can be crucial in establishing neurotransmitter phenotypes and altering early neuronal excitability.

}, keywords = {Animals, Calcium Signaling, Cells, Cultured, Coculture Techniques, Myoblasts, Neurons, Neurotransmitter Agents, Xenopus laevis}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.5659-09.2010}, author = {Xiao, Qian and Xu, Lin and Spitzer, Nicholas C} } @article {131, title = {Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction.}, journal = {Proc Natl Acad Sci U S A}, volume = {104}, year = {2007}, month = {2007 Jan 2}, pages = {335-40}, abstract = {

Signaling in the nervous system requires matching of neurotransmitter receptors with cognate neurotransmitters at synapses. The vertebrate neuromuscular junction is the best studied cholinergic synapse, but the mechanisms by which acetylcholine is matched with acetylcholine receptors are not fully understood. Because alterations in neuronal calcium spike activity alter transmitter specification in embryonic spinal neurons, we hypothesized that receptor expression in postsynaptic cells follows changes in transmitter expression to achieve this specific match. We find that embryonic vertebrate striated muscle cells normally express receptors for glutamate, GABA, and glycine as well as for acetylcholine. As maturation progresses, acetylcholine receptor expression prevails. Receptor selection is altered when early neuronal calcium-dependent activity is perturbed, and remaining receptor populations parallel changes in transmitter phenotype. In these cases, glutamatergic, GABAergic, and glycinergic synaptic currents are recorded from muscle cells, demonstrating that activity regulates matching of transmitters and their receptors in the assembly of functional synapses.

}, keywords = {Animals, Calcium, Gene Expression Regulation, Developmental, Muscle, Skeletal, Neuromuscular Junction, Neurotransmitter Agents, Receptors, Neurotransmitter, Spinal Cord, Synapses, Xenopus}, issn = {0027-8424}, doi = {10.1073/pnas.0607450104}, author = {Borodinsky, Laura N and Spitzer, Nicholas C} } @article {130, title = {Activity-dependent homeostatic specification of transmitter expression in embryonic neurons.}, journal = {Nature}, volume = {429}, year = {2004}, month = {2004 Jun 3}, pages = {523-30}, abstract = {

Neurotransmitters are essential for interneuronal signalling, and the specification of appropriate transmitters in differentiating neurons has been related to intrinsic neuronal identity and to extrinsic signalling proteins. Here we show that altering the distinct patterns of Ca2+ spike activity spontaneously generated by different classes of embryonic spinal neurons in vivo changes the transmitter that neurons express without affecting the expression of markers of cell identity. Regulation seems to be homeostatic: suppression of activity leads to an increased number of neurons expressing excitatory transmitters and a decreased number of neurons expressing inhibitory transmitters; the reverse occurs when activity is enhanced. The imposition of specific spike frequencies in vitro does not affect labels of cell identity but again specifies the expression of transmitters that are inappropriate for the markers they express, during an early critical period. The results identify a new role of patterned activity in development of the central nervous system.

}, keywords = {Action Potentials, Animals, Calcium, Calcium Signaling, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Homeostasis, Humans, Neurons, Neurotransmitter Agents, Organ Specificity, Phenotype, Potassium Channels, Inwardly Rectifying, Rats, Sodium Channels, Spinal Cord, Xenopus laevis}, issn = {1476-4687}, doi = {10.1038/nature02518}, author = {Borodinsky, Laura N and Root, Cory M and Cronin, Julia A and Sann, Sharon B and Gu, Xiaonan and Spitzer, Nicholas C} }