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  1. ; ; ( , Methods in molecular biology)
    Dempski, Robert (Ed.)
    This paper describes research methods to investigate the development of synaptic connections between transplanted GABAergic interneurons and endogenous neurons in the adult mouse hippocampus. Our protocol highlights methods for retroviral labeling adult-born GCs, one of the few cell types in the adult brain to be continuously renewed throughout life. By precise targeting of the retrovirus, labeling of adult-born GCs can be combined with optogenetic stimulation of the transplanted cells and electrophysiology in brain slices, to test whether the GABAergic interneurons integrate and establish inhibitory synaptic connections with host brain neurons. Modifications to adult neurogenesis are an important contributing factor inmore »the development and severity of TLE and seizures. When combined with retroviral labeling, the approaches we describe in this chapter can be used to determine whether transplantation modifies the process of adult neurogenesis or other properties of the hippocampus. These approaches are helping to define parameters for potential cell replacement therapies to be used in patients with intractable seizure disorders.« less
    Free, publicly-accessible full text available January 12, 2023
  2. ( , Developmental Biology)
    Free, publicly-accessible full text available October 1, 2022
  3. ; ; ; ( , Journal of Comparative Neurology)
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  4. ; ; ( , G3 Genes|Genomes|Genetics)
    Lott, S (Ed.)
    Abstract Tissue function is dependent on correct cellular organization and behavior. As a result, the identification and study of genes that contribute to tissue morphogenesis is of paramount importance to the fields of cell and developmental biology. Many of the genes required for tissue patterning and organization are highly conserved between phyla. This has led to the emergence of several model organisms and developmental systems that are used to study tissue morphogenesis. One such model is the Drosophila melanogaster pupal eye that has a highly stereotyped arrangement of cells. In addition, the pupal eye is postmitotic that allows for themore »study of tissue morphogenesis independent from any effects of proliferation. While the changes in cell morphology and organization that occur throughout pupal eye development are well documented, less is known about the corresponding transcriptional changes that choreograph these processes. To identify these transcriptional changes, we dissected wild-type Canton S pupal eyes and performed RNA-sequencing. Our analyses identified differential expression of many loci that are documented regulators of pupal eye morphogenesis and contribute to multiple biological processes including signaling, axon projection, adhesion, and cell survival. We also identified differential expression of genes not previously implicated in pupal eye morphogenesis such as components of the Toll pathway, several non-classical cadherins, and components of the muscle sarcomere, which could suggest these loci function as novel patterning factors.« less
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  5. ; ; ; ; ; ; ; ; ( , Developmental Neurobiology)
    During embryonic development of bilaterally symmetrical organisms, neurons send axons across the midline at specific points to connect the two halves of the nervous system with a commissure. Little is known about the cells at the midline that facilitate this tightly regulated process. We exploit the conserved process of vertebrate embryonic development in the zebrafish model system to elucidate the identity of cells at the midline that may facilitate postoptic (POC) and anterior commissure (AC) development. We have discovered that three different gfap+ astroglial cell morphologies persist in contact with pathfinding axons throughout commissure formation. Similarly, olig2+ progenitor cells occupymore »delineated portions of the postoptic and anterior commissures where they act as multipotent, neural progenitors. Moreover, we conclude that both gfap+ and olig2+ progenitor cells give rise to neuronal populations in both the telencephalon and diencephalon; however, these varied cell populations showed significant developmental timing differences between the telencephalon and diencephalon. Lastly, we also showed that fli1a+ mesenchymal cells migrate along the presumptive commissure regions before and during midline axon crossing. Furthermore, following commissure maturation, specific blood vessels formed at the midline of the POC and immediately ventral and parallel to the AC. This comprehensive account of the cellular populations that correlate with the timing and position of commissural axon pathfinding has supported the conceptual modeling and identification of the early forebrain architecture that may be necessary for proper commissure development.« less
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  6. ; ; ; ( , Developmental Biology)
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  7. ; ( , Bioprotocol)
    In the pilocarpine model of temporal lobe epilepsy (TLE) in rodents, systemic injections of pilocarpine induce continuous, prolonged limbic seizures, a condition termed “Status Epilepticus” (SE). With appropriate doses, many inbred strains of mice show behavioral seizures within an hour after pilocarpine is injected. With the behavioral scoring system based on a modification of the original Racine scale, one can monitor the seizures behaviorally, as they develop into more prolonged seizures and SE. SE is typically associated with damage to subsets of hippocampal neurons and other structural changes in the hippocampus and generally subsides on its own. However, more precisemore »control of the duration of SE is commonly achieved by injecting a benzodiazepine into the mouse 1 to 3 h after the onset of SE to suppress the seizures. Several days following pilocarpine-induced SE, electrographic and behavioral seizures begin to occur spontaneously. The goal of this protocol is to reliably generate mice that develop spontaneous recurrent seizures (SRS) and show the typical neuropathological changes in the brain characteristic of severe human mesial temporal lobe epilepsy (mTLE), without high mortality. To reduce mortality, multiple subthreshold injections of pilocarpine are administered, which increases the percentage of mice developing SE without concomitant mortality. Precise control of the duration of SE (1 or 3 h) is achieved by suppressing SE with the benzodiazepine Midazolam (Versed). We have found that this protocol is an efficient means for generating mice that subsequently develop characteristics of human mTLE including high-frequency interictal spike and wave activity and SRS. In addition, we and others have shown that this protocol produces mice that show excitotoxic cell death of subsets of hippocampal GABAergic interneurons, particularly in the dentate gyrus and compensatory sprouting of excitatory projections from dentate granule cells (mossy fiber sprouting). Aspects of this protocol have been described in several of our previous publications.« less
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  8. ; ; ; ( , PloS one)
    Transplantation of human embryonic stem cell (hESC)-derived neural progenitors is a potential treatment for neurological disorders, but relatively little is known about the time course for human neuron maturation after transplantation and the emergence of morphological and electrophysiological properties. To address this gap, we transplanted hESC-derived human GABAergic interneuron progenitors into the mouse hippocampus, and then characterized their electrophysiological properties and dendritic arborizations after transplantation by means of ex vivo whole-cell patch clamp recording, followed by biocytin staining, confocal imaging and neuron reconstruction software. We asked whether particular electrophysiological and morphological properties showed maturation-dependent changes after transplantation. We also investigatedmore »whether the emergence of particular electrophysiological properties were linked to increased complexity of the dendritic arbors. Human neurons were classified into five distinct neuronal types (Type I-V), ranging from immature to mature fastspiking interneurons. Hierarchical clustering of the dendritic morphology and Sholl analyses suggested four morphologically distinct classes (Class A-D), ranging from simple/immature to highly complex. Incorporating all of our data regardless of neuronal classification, we investigated whether any electrophysiological and morphological features correlated with time post-transplantation. This analysis demonstrated that both dendritic arbors and electrophysiological properties matured after transplantation.« less
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  9. ; ; ( , Encyclopedia of life sciences)
    The Drosophila eye is an outstanding model system for exploring fundamental mechanisms of growth and development. The adult eye is composed of a perfect hexagonal lattice of ∼750 unit eyes, or ommatidia, each containing precisely 20 well-characterized cells. The eye develops from the eye/antennal imaginal disc, a flattened epithelial sac. During larval and pupal development, cells in the disc grow and undergo compartmentalisation, cell cycle arrest, differentiation, directed movement, and apoptosis, all utilising gene networks and signalling pathways similar to those in vertebrates. The genetic accessibility of Drosophila, together with the precision of eye development, makes the fly retina anmore »extremely useful system with which to investigate the roles of genes and signalling pathways in development.« less
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  10. ; ; ; ; ; ; ; ( , ENeuro)
    The dentate gyrus (DG) is a region of the adult rodent brain that undergoes continuous neurogenesis. Seizures and loss or dysfunction of GABAergic synapses onto adult-born dentate granule cells (GCs) alter their dendritic growth and migration, resulting in dysmorphic and hyperexcitable GCs. Additionally, transplants of fetal GABAergic interneurons in the DG of mice with temporal lobe epilepsy (TLE) result in seizure suppression, but it is unknown whether increasing interneurons with these transplants restores GABAergic innervation to adult-born GCs. Here we address this question by retroviral birth-dating GCs at different times up to 12 weeks after pilocarpine-induced TLE in adult mice.more »ChR2-EYFP-expressing MGE-derived GABAergic interneurons from E13.5 mouse embryos were transplanted into the DG of the TLE mice and GCs with transplant-derived inhibitory post-synaptic currents were identified by patch-clamp electrophysiology and optogenetic interrogation. Putative synaptic sites between GCs and GABAergic transplants were also confirmed by intracellular biocytin staining, immunohistochemistry, and confocal imaging. 3D reconstructions of dendritic arbors and quantitative morphometric analyses were carried out in >150 adult-born GCs. GABAergic inputs from transplanted interneurons correlated with markedly shorter GC dendrites, compared to GCs that were not innervated by the transplants. Moreover, these effects were confined to distal dendritic branches and a short time window of 6-8 weeks. The effects were independent of seizures as they were also observed in naïve mice with MGE transplants. These findings are consistent with the hypothesis that increased inhibitory currents over a smaller dendritic arbor in adult-born GCs may reduce their excitability and lead to seizure suppression.« less
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