@article {1684, title = {Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {2017 01 24}, pages = {E610-E618}, abstract = {

The signaling mechanisms that choreograph the assembly of the highly asymmetric pre- and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of \~{}50\% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of \~{}50\% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.

}, keywords = {Animals, Behavior, Animal, Cadherins, Cell Polarity, Cells, Cultured, Excitatory Postsynaptic Potentials, Glutamic Acid, Hippocampus, Locomotion, Male, Maze Learning, Mice, Knockout, Nerve Tissue Proteins, Pyramidal Cells, Receptors, Cell Surface, Synapses, Wnt-5a Protein}, issn = {1091-6490}, doi = {10.1073/pnas.1612062114}, author = {Thakar, Sonal and Wang, Liqing and Yu, Ting and Ye, Mao and Onishi, Keisuke and Scott, John and Qi, Jiaxuan and Fernandes, Catarina and Han, Xuemei and Yates, John R and Berg, Darwin K and Zou, Yimin} } @article {140, title = {Non-cell-autonomous mechanism of activity-dependent neurotransmitter switching.}, journal = {Neuron}, volume = {82}, year = {2014}, month = {2014 Jun 4}, pages = {1004-16}, abstract = {

Activity-dependent neurotransmitter switching engages genetic programs regulating transmitter synthesis, but the mechanism by which activity is transduced is unknown. We suppressed activity in single neurons in the embryonic spinal cord to determine whether glutamate-gamma-aminobutyric acid (GABA) switching is cell autonomous. Transmitter respecification did not occur, suggesting that it is homeostatically regulated by the level of activity in surrounding neurons. Graded increase in the number of silenced neurons in cultures led to graded decrease in the number of neurons expressing GABA, supporting non-cell-autonomous transmitter switching. We found that brain-derived neurotrophic factor (BDNF) is expressed in the spinal cord during the period of transmitter respecification and that spike activity causes release of BDNF. Activation of TrkB receptors triggers a signaling cascade involving JNK-mediated activation of cJun that regulates tlx3, a glutamate/GABA selector gene, accounting for calcium-spike BDNF-dependent transmitter switching. Our findings identify a molecular mechanism for activity-dependent respecification of neurotransmitter phenotype in developing spinal neurons.

}, keywords = {Animals, Brain-Derived Neurotrophic Factor, Calcium, Cells, Cultured, Female, gamma-Aminobutyric Acid, Glutamic Acid, JNK Mitogen-Activated Protein Kinases, Neurons, Phosphorylation, Proto-Oncogene Proteins c-jun, Signal Transduction, Spinal Cord, Xenopus laevis}, issn = {1097-4199}, doi = {10.1016/j.neuron.2014.04.029}, author = {Guemez-Gamboa, Alicia and Xu, Lin and Meng, Da and Spitzer, Nicholas C} } @article {132, title = {Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification.}, journal = {J Neurosci}, volume = {28}, year = {2008}, month = {2008 Apr 30}, pages = {4777-84}, abstract = {

Neurotransmitter signaling in the mature nervous system is well understood, but the functions of transmitters in the immature nervous system are less clear. Although transmitters released during embryogenesis regulate neuronal proliferation and migration, little is known about their role in regulating early neuronal differentiation. Here, we show that GABA and glutamate drive calcium-dependent embryonic electrical activity that regulates transmitter specification. The number of neurons expressing different transmitters changes when GABA or glutamate signaling is blocked chronically, either using morpholinos to knock down transmitter-synthetic enzymes or applying pharmacological receptor antagonists during a sensitive period of development. We find that calcium spikes are triggered by metabotropic GABA and glutamate receptors, which engage protein kinases A and C. The results reveal a novel role for embryonically expressed neurotransmitters.

}, keywords = {Animals, Antigens, CD57, Calcium, Choline O-Acetyltransferase, Embryo, Nonmammalian, Enzyme Inhibitors, Excitatory Amino Acid Antagonists, GABA Antagonists, gamma-Aminobutyric Acid, Gene Expression Regulation, Developmental, Glutamate Decarboxylase, Glutamic Acid, Health Services Research, Larva, Morpholines, Neurons, Phosphoserine, Receptors, GABA, Receptors, Glutamate, Synapses, Vesicular Glutamate Transport Proteins, Xenopus}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4873-07.2008}, author = {Root, Cory M and Vel{\'a}zquez-Ulloa, Norma A and Monsalve, Gabriela C and Minakova, Elena and Spitzer, Nicholas C} }