@article {127, title = {Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.}, journal = {Nature}, volume = {527}, year = {2015}, month = {2015 Nov 5}, pages = {95-9}, abstract = {

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15\% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

}, keywords = {Action Potentials, Antipsychotic Agents, Bipolar Disorder, Calcium Signaling, Dentate Gyrus, Endophenotypes, Humans, Induced Pluripotent Stem Cells, Lithium Compounds, Male, Mitochondria, Neurons, Patch-Clamp Techniques}, issn = {1476-4687}, doi = {10.1038/nature15526}, author = {Mertens, Jerome and Wang, Qiu-Wen and Kim, Yongsung and Yu, Diana X and Pham, Son and Yang, Bo and Zheng, Yi and Diffenderfer, Kenneth E and Zhang, Jian and Soltani, Sheila and Eames, Tameji and Schafer, Simon T and Boyer, Leah and Marchetto, Maria C and Nurnberger, John I and Calabrese, Joseph R and {\O}degaard, Ketil J and McCarthy, Michael J and Zandi, Peter P and Alda, Martin and Alba, Martin and Nievergelt, Caroline M and Mi, Shuangli and Brennand, Kristen J and Kelsoe, John R and Gage, Fred H and Yao, Jun} } @article {138, title = {Activity-dependent competition regulates motor neuron axon pathfinding via PlexinA3.}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, year = {2013}, month = {2013 Jan 22}, pages = {1524-9}, abstract = {

The role of electrical activity in axon guidance has been extensively studied in vitro. To better understand its role in the intact nervous system, we imaged intracellular Ca(2+) in zebrafish primary motor neurons (PMN) during axon pathfinding in vivo. We found that PMN generate specific patterns of Ca(2+) spikes at different developmental stages. Spikes arose in the distal axon of PMN and were propagated to the cell body. Suppression of Ca(2+) spiking activity in single PMN led to stereotyped errors, but silencing all electrical activity had no effect on axon guidance, indicating that an activity-based competition rule regulates this process. This competition was not mediated by synaptic transmission. Combination of PlexinA3 knockdown with suppression of Ca(2+) activity in single PMN produced a synergistic increase in the incidence of pathfinding errors. However, expression of PlexinA3 transcripts was not regulated by activity. Our results provide an in vivo demonstration of the intersection of spontaneous electrical activity with the PlexinA3 guidance molecule receptor in regulation of axon pathfinding.

}, keywords = {Animals, Animals, Genetically Modified, Axons, Calcium Signaling, Gene Knockdown Techniques, Humans, Motor Neurons, Neural Pathways, Potassium Channels, Inwardly Rectifying, Receptors, Cell Surface, Recombinant Proteins, Synaptic Transmission, Zebrafish, Zebrafish Proteins}, issn = {1091-6490}, doi = {10.1073/pnas.1213048110}, author = {Plazas, Paola V and Nicol, Xavier 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 {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} }