Loss-of-huntingtin in medial and lateral ganglionic lineages differentially disrupts regional interneuron and projection neuron subtypes and promotes huntington’s disease-associated behavioral, cellular, and pathological hallmarks

Mark F. Mehler, Jenna R. Petronglo, Eduardo E. Arteaga-Bracho, Maria E. Gulinello, Michael L. Winchester, Nandini Pichamoorthy, Stephen K. Young, Christopher D. Dejesus, Hifza Ishtiaq, Solen Gokhan, Aldrin E. Molero

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Emerging studies are providing compelling evidence that the pathogenesis of Huntington’s disease (HD), a neurodegenerative disorder with frequent midlife onset, encompasses developmental components. Moreover, our previous studies using a hypomorphic model targeting huntingtin during the neurodevelopmental period indicated that loss-of-function mechanisms account for this pathogenic developmental component (Arteaga-Bracho et al., 2016). In the present study, we specifically ascertained the roles of subpallial lineage species in eliciting the previously observed HD-like phenotypes. Accordingly, we used the Cre-loxP system to conditionally ablate the murine huntingtin gene (Htt flx ) in cells expressing the subpallial patterning markers Gsx2 (Gsx2-Cre) or Nkx2.1 (Nkx2.1-Cre) in Htt flx mice of both sexes. These genetic manipulations elicited anxiety-like behaviors, hyperkinetic locomotion, age-dependent motor deficits, and weight loss in both Htt flx ;Gsx2-Cre and Htt flx ;Nkx2.1-Cre mice. In addition, these strains displayed unique but complementary spatial patterns of basal ganglia degeneration that are strikingly reminiscent of those seen in human cases of HD. Furthermore, we observed early deficits of somatostatin-positive and Reelin-positive interneurons in both Htt subpallial null strains, as well as early increases of cholinergic interneurons, Foxp2 + arkypallidal neurons, and incipient deficits with age-dependent loss of parvalbumin-positive neurons in Htt flx ;Nkx2.1-Cre mice. Overall, our findings indicate that selective loss-of-huntingtin function in subpallial lineages differentially disrupts the number, complement, and survival of forebrain interneurons and globus pallidus GABAergic neurons, thereby leading to the development of key neurological hallmarks of HD during adult life. Our findings have important implications for the establishment and deployment of neural circuitries and the integrity of network reserve in health and disease.

Original languageEnglish (US)
Pages (from-to)1892-1909
Number of pages18
JournalJournal of Neuroscience
Volume39
Issue number10
DOIs
StatePublished - Mar 6 2019

Fingerprint

Huntington Disease
Interneurons
Neurons
GABAergic Neurons
Parvalbumins
Globus Pallidus
Locomotion
Prosencephalon
Somatostatin
Basal Ganglia
Neurodegenerative Diseases
Cholinergic Agents
Weight Loss
Anxiety
Phenotype
Health
Genes

Keywords

  • Cell vulnerability
  • Development
  • Interneurons
  • Neurodegeneration
  • Pathogenesis
  • Subpallium

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Loss-of-huntingtin in medial and lateral ganglionic lineages differentially disrupts regional interneuron and projection neuron subtypes and promotes huntington’s disease-associated behavioral, cellular, and pathological hallmarks. / Mehler, Mark F.; Petronglo, Jenna R.; Arteaga-Bracho, Eduardo E.; Gulinello, Maria E.; Winchester, Michael L.; Pichamoorthy, Nandini; Young, Stephen K.; Dejesus, Christopher D.; Ishtiaq, Hifza; Gokhan, Solen; Molero, Aldrin E.

In: Journal of Neuroscience, Vol. 39, No. 10, 06.03.2019, p. 1892-1909.

Research output: Contribution to journalArticle

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abstract = "Emerging studies are providing compelling evidence that the pathogenesis of Huntington’s disease (HD), a neurodegenerative disorder with frequent midlife onset, encompasses developmental components. Moreover, our previous studies using a hypomorphic model targeting huntingtin during the neurodevelopmental period indicated that loss-of-function mechanisms account for this pathogenic developmental component (Arteaga-Bracho et al., 2016). In the present study, we specifically ascertained the roles of subpallial lineage species in eliciting the previously observed HD-like phenotypes. Accordingly, we used the Cre-loxP system to conditionally ablate the murine huntingtin gene (Htt flx ) in cells expressing the subpallial patterning markers Gsx2 (Gsx2-Cre) or Nkx2.1 (Nkx2.1-Cre) in Htt flx mice of both sexes. These genetic manipulations elicited anxiety-like behaviors, hyperkinetic locomotion, age-dependent motor deficits, and weight loss in both Htt flx ;Gsx2-Cre and Htt flx ;Nkx2.1-Cre mice. In addition, these strains displayed unique but complementary spatial patterns of basal ganglia degeneration that are strikingly reminiscent of those seen in human cases of HD. Furthermore, we observed early deficits of somatostatin-positive and Reelin-positive interneurons in both Htt subpallial null strains, as well as early increases of cholinergic interneurons, Foxp2 + arkypallidal neurons, and incipient deficits with age-dependent loss of parvalbumin-positive neurons in Htt flx ;Nkx2.1-Cre mice. Overall, our findings indicate that selective loss-of-huntingtin function in subpallial lineages differentially disrupts the number, complement, and survival of forebrain interneurons and globus pallidus GABAergic neurons, thereby leading to the development of key neurological hallmarks of HD during adult life. Our findings have important implications for the establishment and deployment of neural circuitries and the integrity of network reserve in health and disease.",
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AU - Mehler, Mark F.

AU - Petronglo, Jenna R.

AU - Arteaga-Bracho, Eduardo E.

AU - Gulinello, Maria E.

AU - Winchester, Michael L.

AU - Pichamoorthy, Nandini

AU - Young, Stephen K.

AU - Dejesus, Christopher D.

AU - Ishtiaq, Hifza

AU - Gokhan, Solen

AU - Molero, Aldrin E.

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AB - Emerging studies are providing compelling evidence that the pathogenesis of Huntington’s disease (HD), a neurodegenerative disorder with frequent midlife onset, encompasses developmental components. Moreover, our previous studies using a hypomorphic model targeting huntingtin during the neurodevelopmental period indicated that loss-of-function mechanisms account for this pathogenic developmental component (Arteaga-Bracho et al., 2016). In the present study, we specifically ascertained the roles of subpallial lineage species in eliciting the previously observed HD-like phenotypes. Accordingly, we used the Cre-loxP system to conditionally ablate the murine huntingtin gene (Htt flx ) in cells expressing the subpallial patterning markers Gsx2 (Gsx2-Cre) or Nkx2.1 (Nkx2.1-Cre) in Htt flx mice of both sexes. These genetic manipulations elicited anxiety-like behaviors, hyperkinetic locomotion, age-dependent motor deficits, and weight loss in both Htt flx ;Gsx2-Cre and Htt flx ;Nkx2.1-Cre mice. In addition, these strains displayed unique but complementary spatial patterns of basal ganglia degeneration that are strikingly reminiscent of those seen in human cases of HD. Furthermore, we observed early deficits of somatostatin-positive and Reelin-positive interneurons in both Htt subpallial null strains, as well as early increases of cholinergic interneurons, Foxp2 + arkypallidal neurons, and incipient deficits with age-dependent loss of parvalbumin-positive neurons in Htt flx ;Nkx2.1-Cre mice. Overall, our findings indicate that selective loss-of-huntingtin function in subpallial lineages differentially disrupts the number, complement, and survival of forebrain interneurons and globus pallidus GABAergic neurons, thereby leading to the development of key neurological hallmarks of HD during adult life. Our findings have important implications for the establishment and deployment of neural circuitries and the integrity of network reserve in health and disease.

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