Article

Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants

Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, Maryland 20892, USA.
The Journal of Comparative Neurology (Impact Factor: 3.51). 09/2008; 510(1):79-99. DOI: 10.1002/cne.21772
Source: PubMed

ABSTRACT Here we analyze the role of the Lhx6 lim-homeobox transcription factor in regulating the development of subsets of neocortical, hippocampal, and striatal interneurons. An Lhx6 loss-of-function allele, which expresses placental alkaline phosphatase (PLAP), allowed analysis of the development and fate of Lhx6-expressing interneurons in mice lacking this homeobox transcription factor. There are Lhx6+;Dlx+ and Lhx6-;Dlx+ subtypes of tangentially migrating interneurons. Most interneurons in Lhx6(PLAP/PLAP) mutants migrate to the cortex, although less efficiently, and exhibit defects in populating the marginal zone and superficial parts of the neocortical plate. By contrast, migration to superficial parts of the hippocampus is not seriously affected. Furthermore, whereas parvalbumin+ and somatostatin+ interneurons do not differentiate, NPY+ interneurons are present; we suggest that these NPY+ interneurons are derived from the Lhx6-;Dlx+ subtype. Striatal interneurons show deficits distinct from pallial interneurons, including a reduction in the NPY+ subtype. We provide evidence that Lhx6 mediates these effects through promoting expression of receptors that regulate interneuron migration (ErbB4, CXCR4, and CXCR7), and through promoting the expression of transcription factors either known (Arx) or implicated (bMaf, Cux2, and NPAS1) in controlling interneuron development.

0 Followers
 · 
113 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inhibitory GABAergic interneurons within the cerebral cortex are critical for fi ne-tuning the activity of cortical circuits and thus are thought to be involved in generating the distinct oscillatory patterns that underlie higher brain functions such as consciousness and memory. Understanding how cortical interneurons are speci-fi ed during development is important not just from the standpoint of basic research but also is likely to provide key insights into how cognitive disorders emerge. Although interneurons only consist of around 20 % of the neurons within the neo-cortex, they are extremely diverse with regard to their morphologies, molecular expression profi les, intrinsic electrophysiological properties, and synaptic connec-tions. In rodents, most neocortical interneurons originate during embryogenesis from ventrally located structures, primarily the ganglionic eminences, and therefore must migrate over long distances following discrete pathways to reach the appropriate cortical areas. Thus, proper coordination of the distinct migration programs followed by pyramidal cells and interneuron precursors during development is crucial for the assembly of functional microcircuits within the cerebral cortex. Here, we review and discuss emerging views of how cortical GABAergic interneuron specifi cation, migra-tion, and integration occur from embryonic to early postnatal stages.
    Cortical Development: Neural Diversity and Neocortical Organization, Edited by R. Kageyama and T. Yamamori, 10/2013: chapter 5: pages 89-126; Springer.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia etiology is thought to involve an interaction between genetic and environmental factors during postnatal brain development. However, there is a fundamental gap in our understanding of the molecular mechanisms by which environmental factors interact with genetic susceptibility to trigger symptom onset and disease progression. In this review, we summarize the most recent findings implicating oxidative stress as one mechanism by which environmental insults, especially early life social stress, impact the development of schizophrenia. Based on a review of the literature and the results of our own animal model, we suggest that environmental stressors such as social isolation render parvalbumin-positive interneurons (PVIs) vulnerable to oxidative stress. We previously reported that social isolation stress exacerbates many of the schizophrenia-like phenotypes seen in a conditional genetic mouse model in which NMDA receptors (NMDARs) are selectively ablated in half of cortical and hippocampal interneurons during early postnatal development (Belforte et al., 2010). We have since revealed that this social isolation-induced effect is caused by impairments in the antioxidant defense capacity in the PVIs in which NMDARs are ablated. We propose that this effect is mediated by the down-regulation of PGC-1α, a master regulator of mitochondrial energy metabolism and anti-oxidant defense, following the deletion of NMDARs (Jiang et al., 2013). Other potential molecular mechanisms underlying redox dysfunction upon gene and environmental interaction will be discussed, with a focus on the unique properties of PVIs.
    Frontiers in Behavioral Neuroscience 09/2013; 7:116. DOI:10.3389/fnbeh.2013.00116 · 4.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This study investigated the distribution of neuropeptide Y (NPY) in the brain of the night-migratory redheaded bunting (Emberiza bruniceps). We first cloned the 275-bp NPY gene in buntings, with ≥95 % homology with known sequences from other birds. The deduced peptide sequence contained all conserved 36 amino acids chain of the mature NPY peptide, but lacked 6 amino acids that form the NPY signal peptide. Using digosigenin-labeled riboprobe prepared from the cloned sequence, the brain cells that synthesize NPY were identified by in-situ hybridization. The NPY peptide containing cell bodies and terminals (fibers) were localized by immunocytochemistry. NPY mRNA and peptide were widespread throughout the bunting brain. This included predominant pallial and sub-pallial areas (cortex piriformis, cortex prepiriformis, hyperpallium apicale, hippocampus, globus pallidus) and thalamic and hypothalamic nuclei (organum vasculosum laminae terminalis, nucleus (n.) dorsolateralis anterior thalami, n. rotundus, n. infundibularis) including the median eminence and hind brain (n. pretectalis, n. opticus basalis, n. reticularis pontis caudalis pars gigantocellularis). The important structures with only NPY-immunoreactive fibers included the olfactory bulb, medial and lateral septal areas, medial preoptic nucleus, medial suprachiasmatic nucleus, paraventricular nucleus, ventromedial hypothalamic nucleus, optic tectum, and ventro-lateral geniculate nucleus. These results demonstrate that NPY is possibly involved in the regulation of several physiological functions (e.g. daily timing feeding, and reproduction) in the migratory bunting.
    Cell and Tissue Research 06/2013; 354(2). DOI:10.1007/s00441-013-1667-x · 3.33 Impact Factor

Preview

Download
4 Downloads
Available from