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

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 ϩ arkypallidal neurons, and incipient deficits with age-dependent loss of parvalbuminpositive 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.

Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival

“…Wild-type HTT plays critical roles in cell health and viability. Global knockout of Htt in mice is embryonically lethal, and loss of HTT in progenitor cells leads to impairments in cell proliferation, migration, and survival (Godin et al, 2010;Elias et al, 2015;Tong et al, 2011;Mehler et al, 2019;Nasir et al, 1995). Furthermore, Htt cKO in mouse cortical neurons leads to synaptic dysfunction, cell stress and neuroinflammation, and neuronal death (Dragatsis et al, 2000;McKinstry et al, 2014).…”

“…However, the pattern of degeneration does not resemble the striatum-specific SPN loss seen in HD. Deleting Htt from cells of subpallidal lineage using Gsx2-Cre causes hyperlocomotion during early adulthood and agingdependent neuronal loss (Mehler et al, 2019). However, Gsx2-Cre is not specific for SPNs; all progenitors from the lateral ganglionic eminence are targeted, including oligodendrocytes and interneurons.…”

“…health and viability, because deleting Htt in the mouse central nervous system leads to aberrant synaptic connectivity, cellular stress, neuroinflammation, and neuronal death (McKinstry et al, 2014;Dragatsis et al, 2000Dragatsis et al, , 2018Mehler et al, 2019). On the other hand, wild-type HTT is neuroprotective and can shield neurons against mHTT toxicity (Leavitt et al, 2006).…”

Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids

“…Studies in mouse models support this notion and have demonstrated a role for normal HTT in brain development. Loss of HTT has been shown to cause profound neurodevelopmental abnormalities, including striatal and cortical malformation [9][10][11]. In early corticogenesis, HTT was shown to be required for proper mitotic spindle orientation, a key determinant of cortical progenitor fate [12].…”

Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations

“…Other studies have shown that embryonic, conditional deletion of HTT from cortical pyramidal neurons (CPNs) reduced cortical volume and neuron abundance (Dragatsis et al, ). Similarly, loss of HTT function in subpallial lineages disrupted forebrain interneuron species early in life and also led to a number of neurological deficits reminiscent of HD (Mehler et al, ).…”