@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 {183, title = {Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice.}, journal = {Elife}, volume = {2}, year = {2013}, month = {2013}, pages = {e00312}, abstract = {

The hippocampus is critical for episodic memory and computational studies have predicted specific functions for each hippocampal subregion. Particularly, the dentate gyrus (DG) is hypothesized to perform pattern separation by forming distinct representations of similar inputs. How pattern separation is achieved by the DG remains largely unclear. By examining neuronal activities at a population level, we revealed that, unlike CA1 neuron populations, dentate granule cell (DGC) ensembles activated by learning were not preferentially reactivated by memory recall. Moreover, when mice encountered an environment to which they had not been previously exposed, a novel DGC population-rather than the previously activated DGC ensembles that responded to past events-was selected to represent the new environmental inputs. This selection of a novel responsive DGC population could be triggered by small changes in environmental inputs. Therefore, selecting distinct DGC populations to represent similar but not identical inputs is a mechanism for pattern separation. DOI:http://dx.doi.org/10.7554/eLife.00312.001.

}, keywords = {Animals, Behavior, Animal, Brain Mapping, CA1 Region, Hippocampal, Conditioning (Psychology), Cues, Dentate Gyrus, Environment, Fear, Gene Expression Regulation, Genes, Reporter, Memory, Memory, Episodic, Mental Recall, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Neural Pathways, Neurons, Pattern Recognition, Physiological, Time Factors}, issn = {2050-084X}, doi = {10.7554/eLife.00312}, author = {Deng, Wei and Mayford, Mark and Gage, Fred H} } @article {175, title = {Computational influence of adult neurogenesis on memory encoding.}, journal = {Neuron}, volume = {61}, year = {2009}, month = {2009 Jan 29}, pages = {187-202}, abstract = {

Adult neurogenesis in the hippocampus leads to the incorporation of thousands of new granule cells into the dentate gyrus every month, but its function remains unclear. Here, we present computational evidence that indicates that adult neurogenesis may make three separate but related contributions to memory formation. First, immature neurons introduce a degree of similarity to memories learned at the same time, a process we refer to as pattern integration. Second, the extended maturation and change in excitability of these neurons make this added similarity a time-dependent effect, supporting the possibility that temporal information is included in new hippocampal memories. Finally, our model suggests that the experience-dependent addition of neurons results in a dentate gyrus network well suited for encoding new memories in familiar contexts while treating novel contexts differently. Taken together, these results indicate that new granule cells may affect hippocampal function in several unique and previously unpredicted ways.

}, keywords = {Age Factors, Algorithms, Animals, Cell Proliferation, Computer Simulation, Dentate Gyrus, Humans, Memory, Nerve Net, Neural Pathways, Neurogenesis, Neuronal Plasticity, Neurons, Stem Cells, Synapses, Time Perception}, issn = {1097-4199}, doi = {10.1016/j.neuron.2008.11.026}, author = {Aimone, James B and Wiles, Janet and Gage, Fred H} }