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Molecular and Cellular Neurosciences Jun 2016Compelling clinical, social, and economic reasons exist to innovate in the process of drug discovery for neuropsychiatric disorders. The use of patient-specific, induced... (Review)
Review
Compelling clinical, social, and economic reasons exist to innovate in the process of drug discovery for neuropsychiatric disorders. The use of patient-specific, induced pluripotent stem cells (iPSCs) now affords the ability to generate neuronal cell-based models that recapitulate key aspects of human disease. In the context of neuropsychiatric disorders, where access to physiologically active and relevant cell types of the central nervous system for research is extremely limiting, iPSC-derived in vitro culture of human neurons and glial cells is transformative. Potential applications relevant to early stage drug discovery, include support of quantitative biochemistry, functional genomics, proteomics, and perhaps most notably, high-throughput and high-content chemical screening. While many phenotypes in human iPSC-derived culture systems may prove adaptable to screening formats, addressing the question of which in vitro phenotypes are ultimately relevant to disease pathophysiology and therefore more likely to yield effective pharmacological agents that are disease-modifying treatments requires careful consideration. Here, we review recent examples of studies of neuropsychiatric disorders using human stem cell models where cellular phenotypes linked to disease and functional assays have been reported. We also highlight technical advances using genome-editing technologies in iPSCs to support drug discovery efforts, including the interpretation of the functional significance of rare genetic variants of unknown significance and for the purpose of creating cell type- and pathway-selective functional reporter assays. Additionally, we evaluate the potential of in vitro stem cell models to investigate early events of disease pathogenesis, in an effort to understand the underlying molecular mechanism, including the basis of selective cell-type vulnerability, and the potential to create new cell-based diagnostics to aid in the classification of patients and subsequent selection for clinical trials. A number of key challenges remain, including the scaling of iPSC models to larger cohorts and integration with rich clinicopathological information and translation of phenotypes. Still, the overall use of iPSC-based human cell models with functional cellular and biochemical assays holds promise for supporting the discovery of next-generation neuropharmacological agents for the treatment and ultimately prevention of a range of severe mental illnesses.
Topics: Cell Culture Techniques; Drug Discovery; Humans; Induced Pluripotent Stem Cells; Mental Disorders; Models, Biological; Neurons; Precision Medicine
PubMed: 26826498
DOI: 10.1016/j.mcn.2016.01.011 -
Psychiatry and Clinical Neurosciences Sep 2017The etiology of neuropsychiatric disorders, such as schizophrenia and bipolar disorder, usually involves complex combinations of genetic defects/variations and... (Review)
Review
The etiology of neuropsychiatric disorders, such as schizophrenia and bipolar disorder, usually involves complex combinations of genetic defects/variations and environmental impacts, which hindered, for a long time, research efforts based on animal models and patients' non-neuronal cells or post-mortem tissues. However, the development of human induced pluripotent stem cell (iPSC) technology by the Yamanaka group was immediately applied to establish cell research models for neuronal disorders. Since then, techniques to achieve highly efficient differentiation of different types of neural cells following iPSC modeling have made much progress. The fast-growing iPSC and neural differentiation techniques have brought valuable insights into the pathology and neurobiology of neuropsychiatric disorders. In this article, we first review the application of iPSC technology in modeling neuronal disorders and discuss the progress in the accompanying neural differentiation. Then, we summarize the progress in iPSC-based research that has been accomplished so far regarding schizophrenia and bipolar disorder.
Topics: Animals; Bipolar Disorder; Humans; Induced Pluripotent Stem Cells; Neurons; Schizophrenia
PubMed: 28393474
DOI: 10.1111/pcn.12528 -
The Journal of General Physiology Mar 1956Cross sections of olfactory nerves present a unique appearance. They indicate the presence of large numbers of very small nerve fibers, with a modal diameter of about...
Cross sections of olfactory nerves present a unique appearance. They indicate the presence of large numbers of very small nerve fibers, with a modal diameter of about 0.2 micro and a narrow range for their size variation. From one side of the nasal septum of a pig the yield of fibers was estimated at 6,000,000; the number arising from the turbinates would be considerably larger. The fibers are attached to the membranes of the Schwann sheaths in large bundles through mesaxons longer and more branched than those that have been seen in other nerves. Continuity of the axons between the nerves and the bipolar cells was traced in an examination of the olfactory mucous membrane; and the indication of a one-to-one relationship between cells and axons was reinforced by a comparative count. After the axons leave the bipolar cells they become incased in the central projections of the sustentacular cells. Where the latter come into contact with the basal cells the axons emerge to push back the plasma membranes of the basal cells in the first step in acquiring their nerve sheaths. Later steps are described. When the axons are delivered by the basal cells to the collecting Schwann tubes, they are already aggregated into small bundles with sheaths fundamentally the same as those they will possess until they are delivered to the glia in the olfactory bulb. Some of the aspects of the cytology of the bipolar cells and adjoining sustentacular cells are described. A survey of the physiological properties of olfactory nerve fibers was made in some experiments on the olfactory nerve of the pike. Almost all of the action potential is encompassed within a single elevation, manifesting at its front a conduction velocity of 0.2 m./sec. For a comparison, the last elevation in the C action potential in the sciatic nerve of the frog is cited as an example of conduction at the same velocity. Though expressed through long time constants, the properties of the pike olfactory fibers conform to the generalized schema for properties of vertebrate nerve fibers. This conformity signalizes that they differ from the exceptional properties of the unmedullated fibers of dorsal root origin. An afferent function for unmedullated nerve fibers does not imply that the fibers concerned are alike in their physiological properties.
Topics: Action Potentials; Animals; Axons; Ganglia, Spinal; Neuroglia; Neurons; Olfactory Nerve; Smell; Swine
PubMed: 13295549
DOI: 10.1085/jgp.39.4.473 -
Cell Reports Nov 2019The size of dendrite arbors shapes their function and differs vastly between neuron types. The signals that control dendritic arbor size remain obscure. Here, we find...
The size of dendrite arbors shapes their function and differs vastly between neuron types. The signals that control dendritic arbor size remain obscure. Here, we find that in the retina, starburst amacrine cells (SACs) and rod bipolar cells (RBCs) express the homophilic cell-surface protein AMIGO2. In Amigo2 knockout (KO) mice, SAC and RBC dendrites expand while arbors of other retinal neurons remain stable. SAC dendrites are divided into a central input region and a peripheral output region that provides asymmetric inhibition to direction-selective ganglion cells (DSGCs). Input and output compartments scale precisely with increased arbor size in Amigo2 KO mice, and SAC dendrites maintain asymmetric connectivity with DSGCs. Increased coverage of SAC dendrites is accompanied by increased direction selectivity of DSGCs without changes to other ganglion cells. Our results identify AMIGO2 as a cell-type-specific dendritic scaling factor and link dendrite size and coverage to visual feature detection.
Topics: Action Potentials; Amacrine Cells; Animals; Dendrites; Gene Knockout Techniques; Membrane Proteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Neuronal Plasticity; Retina; Retinal Bipolar Cells; Retinal Ganglion Cells; Synapses
PubMed: 31693896
DOI: 10.1016/j.celrep.2019.09.085 -
Neural Plasticity 2013Adequate maturation of neurons and their integration into the hippocampal circuit is crucial for normal cognitive function and emotional behavior, and disruption of this... (Review)
Review
Adequate maturation of neurons and their integration into the hippocampal circuit is crucial for normal cognitive function and emotional behavior, and disruption of this process could cause disturbances in mental health. Previous reports have shown that mice heterozygous for a null mutation in α -CaMKII, which encodes a key synaptic plasticity molecule, display abnormal behaviors related to schizophrenia and other psychiatric disorders. In these mutants, almost all neurons in the dentate gyrus are arrested at a pseudoimmature state at the molecular and electrophysiological levels, a phenomenon defined as "immature dentate gyrus (iDG)." To date, the iDG phenotype and shared behavioral abnormalities (including working memory deficit and hyperlocomotor activity) have been discovered in Schnurri-2 knockout, mutant SNAP-25 knock-in, and forebrain-specific calcineurin knockout mice. In addition, both chronic fluoxetine treatment and pilocarpine-induced seizures reverse the neuronal maturation, resulting in the iDG phenotype in wild-type mice. Importantly, an iDG-like phenomenon was observed in post-mortem analysis of brains from patients with schizophrenia/bipolar disorder. Based on these observations, we proposed that the iDG is a potential endophenotype shared by certain types of neuropsychiatric disorders. This review summarizes recent data describing this phenotype and discusses the data's potential implication in elucidating the pathophysiology of neuropsychiatric disorders.
Topics: Animals; Dentate Gyrus; Disease Models, Animal; Endophenotypes; Mental Disorders; Mice; Neurons
PubMed: 23840971
DOI: 10.1155/2013/318596 -
Bipolar Disorders Nov 2017Bipolar disorder has been studied from numerous angles, from pathological studies to large-scale genomic studies, overall making moderate gains toward an understanding... (Review)
Review
OBJECTIVES
Bipolar disorder has been studied from numerous angles, from pathological studies to large-scale genomic studies, overall making moderate gains toward an understanding of the disorder. With the advancement of induced pluripotent stem (iPS) cell technology, in vitro models based on patient samples are now available that inherently incorporate the complex genetic variants that largely are the basis for this disorder. A number of groups are starting to apply iPS technology to the study of bipolar disorder.
METHODS
We selectively reviewed the literature related to understanding bipolar disorder based on using neurons derived from iPS cells.
RESULTS
So far, most work has used the prototypical iPS cells. However, others have been able to transdifferentiate fibroblasts directly to neurons. Others still have utilized olfactory epithelium tissue as a source of neural-like cells that do not need reprogramming. In general, iPS and related cells can be used for studies of disease pathology, drug discovery, or stem cell therapy.
CONCLUSIONS
Published studies have primarily focused on understanding bipolar disorder pathology, but initial work is also being done to use iPS technology for drug discovery. In terms of disease pathology, some evidence is pointing toward a differentiation defect with more ventral cell types being prominent. Additionally, there is evidence for a calcium signaling defect, a finding that builds on the genome-wide association study results. Continued work with iPS cells will certainly help us understand bipolar disorder and provide a way forward for improved treatments.
Topics: Animals; Bipolar Disorder; Cell Differentiation; Cell Transdifferentiation; Fibroblasts; Genome-Wide Association Study; Humans; Induced Pluripotent Stem Cells; Neurons; Stem Cell Transplantation
PubMed: 29116664
DOI: 10.1111/bdi.12535 -
Developmental Neurobiology Dec 2011Developing retinal neurons differentiate their distinctive dendritic morphologies through cell-intrinsic instructions and cellular interactions within the local... (Review)
Review
Developing retinal neurons differentiate their distinctive dendritic morphologies through cell-intrinsic instructions and cellular interactions within the local environment. This review examines the contributions of interactions with afferents and with homotypic neighbors upon the dendritic morphogenesis of retinal bipolar cells in four different mouse models that modulate the frequency of these interactions. Comparisons with horizontal cell differentiation are discussed, and differences between the dendritic plasticity within the outer versus inner plexiform layers are highlighted. Finally, the developmental plasticity of the bipolar and horizontal cells is considered in light of the natural variation in afferent and target cell number, ensuring a uniformity of coverage and connectivity across the retinal surface.
Topics: Animals; Dendrites; Mice; Neuronal Plasticity; Retina; Retinal Neurons
PubMed: 21557509
DOI: 10.1002/dneu.20903 -
CNS & Neurological Disorders Drug... Jun 2007Recent research has changed the perception of glia from being no more than silent supportive cells of neurons to being dynamic partners participating in brain metabolism... (Review)
Review
Recent research has changed the perception of glia from being no more than silent supportive cells of neurons to being dynamic partners participating in brain metabolism and communication between neurons. This discovery of new glial functions coincides with growing evidence of the involvement of glia in the neuropathology of mood disorders. Unanticipated reductions in the density and number of glial cells are reported in fronto-limbic brain regions in major depression and bipolar illness. Moreover, age-dependent decreases in the density of glial fibrillary acidic protein (GFAP) - immunoreactive astrocytes and levels of GFAP protein are observed in the prefrontal cortex of younger depressed subjects. Since astrocytes participate in the uptake, metabolism and recycling of glutamate, we hypothesize that an astrocytic deficit may account for the alterations in glutamate/GABA neurotransmission in depression. Reductions in the density and ultrastructure of oligodendrocytes are also detected in the prefrontal cortex and amygdala in depression. Pathological changes in oligodendrocytes may be relevant to the disruption of white matter tracts in mood disorders reported by diffusion tensor imaging. Factors such as stress, excess of glucocorticoids, altered gene expression of neurotrophic factors and glial transporters, and changes in extracellular levels of neurotransmitters released by neurons may modify glial cell number and affect the neurophysiology of depression. Therefore, we will explore the role of these events in the possible alteration of glial number and activity, and the capacity of glia as a promising new target for therapeutic medications. Finally, we will consider the temporal relationship between glial and neuronal cell pathology in depression.
Topics: Animals; Astrocytes; Depressive Disorder; Disease Models, Animal; Humans; Microglia; Neuroglia; Neurons; Oligodendroglia
PubMed: 17511618
DOI: 10.2174/187152707780619326 -
Philosophical Transactions of the Royal... Jul 2015In the mouse retina, dopaminergic amacrine (DA) cells synthesize both dopamine and GABA. Both transmitters are released extrasynaptically and act on neighbouring and... (Review)
Review
In the mouse retina, dopaminergic amacrine (DA) cells synthesize both dopamine and GABA. Both transmitters are released extrasynaptically and act on neighbouring and distant retinal neurons by volume transmission. In simultaneous recordings of dopamine and GABA release from isolated perikarya of DA cells, a proportion of the events of dopamine and GABA exocytosis were simultaneous, suggesting co-release. In addition, DA cells establish GABAergic synapses onto AII amacrine cells, the neurons that transfer rod bipolar signals to cone bipolars. GABAA but not dopamine receptors are clustered in the postsynaptic membrane. Therefore, dopamine, irrespective of its site of release-synaptic or extrasynaptic-exclusively acts by volume transmission. Dopamine is released upon illumination and sets the gain of retinal neurons for vision in bright light. The GABA released at DA cells' synapses probably prevents signals from the saturated rods from entering the cone pathway when the dark-adapted retina is exposed to bright illumination. The GABA released extrasynaptically by DA and other amacrine cells may set a 'GABAergic tone' in the inner plexiform layer and thus counteract the effects of a spillover of glutamate released at the bipolar cell synapses of adjacent OFF and ON strata, thus preserving segregation of signals between ON and OFF pathways.
Topics: Amacrine Cells; Animals; Cell Body; Dopamine; Mice; Synaptic Transmission; Visual Pathways; gamma-Aminobutyric Acid
PubMed: 26009765
DOI: 10.1098/rstb.2014.0186 -
Developmental Biology Oct 2022The development of the dendrite and the axon during neuronal polarization underlies the directed flow of information in the brain. Seminal studies on axon development...
The development of the dendrite and the axon during neuronal polarization underlies the directed flow of information in the brain. Seminal studies on axon development have dominated the mechanistic analysis of neuronal polarization. These studies, many originating from examinations in cultured hippocampal and cortical neurons in vitro, have established a prevalent view that axon formation precedes and is necessary for neuronal polarization. There is also in vivo evidence supporting this view. Nevertheless, the establishment of bipolar polarity, the leading edge, and apical dendrite development in pyramidal neurons in vivo occur when axon formation is prevented. Furthermore, recent mounting evidence suggest that directed mechanisms might mediate bipolar polarity/leading process and subsequent apical dendrite development. In the presence of spatially directed extracellular cues in the developing brain, these events may operate independently of axon forming events. In this perspective we summarize evidence in support of these evolving views in neuronal polarization and highlight recent findings on dedicated mechanisms acting in apical dendrite development.
Topics: Axons; Cell Polarity; Dendrites; Neurogenesis; Neurons
PubMed: 35809631
DOI: 10.1016/j.ydbio.2022.07.002