Effect of early embryonic deletion of huntingtin from pyramidal neurons on the development and long-term survival of neurons in cerebral cortex and striatum

Abstract

We evaluated the impact of early embryonic deletion of huntingtin (htt) from pyramidal neurons on cortical development, cortical neuron survival and motor behavior, using a cre-loxP strategy to inactivate the mouse htt gene (Hdh) in emx1-expressing cell lineages. Western blot confirmed substantial htt reduction in cerebral cortex of these Emx-httKO mice, with residual cortical htt in all likelihood restricted to cortical interneurons of the subpallial lineage and/or vascular endothelial cells. Despite the loss of htt early in development, cortical lamination was normal, as revealed by layer-specific markers. Cortical volume and neuron abundance were, however, significantly less than normal, and cortical neurons showed reduced brain-derived neurotrophic factor (BDNF) expression and reduced activation of BDNF signaling pathways. Nonetheless, cortical volume and neuron abundance did not show progressive age-related decline in Emx-httKO mice out to 24 months. Although striatal neurochemistry was normal, reductions in striatal volume and neuron abundance were seen in Emx-httKO mice, which were again not progressive. Weight maintenance was normal in Emx-httKO mice, but a slight rotarod deficit and persistent hyperactivity were observed throughout the lifespan. Our results show that embryonic deletion of htt from developing pallium does not substantially alter migration of cortical neurons to their correct laminar destinations, but does yield reduced cortical and striatal size and neuron numbers. The Emx-httKO mice were persistently hyperactive, possibly due to defects in corticostriatal development. Importantly, deletion of htt from cortical pyramidal neurons did not yield age-related progressive cortical or striatal pathology.

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

“…Our previous studies have shown that pan-neural loss of Htt function during the murine developmental period leads to motor deficits and hyperkinetic phenotypes expressed during adult life (Arteaga-Bracho et al, 2016). Consistent with our findings, a more recent study reported that deletion of Htt in pallial lineages also results in hyperactivity and motor deficits (Dragatsis et al, 2018). To define whether the selective loss of Htt function in subpallial-derived lineages contribute to HD-like motor abnormalities, we examined motor coordination and free locomotion using the balance beam, rotarod and the open-field tests, respectively.…”

Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival

“…Therefore, three main aspects of HD pathology, abnormal motor function, reactive gliosis, and SPN death, can be partially produced by Htt loss-of-function in SPNs. Previous studies have shown that loss of Htt in forebrain neurons (Dragatsis et al, 2000) or cortex (Dragatsis et al, 2018) leads to widespread cell death, reduced cortical volume, and abnormal motor behavior. However, the pattern of degeneration does not resemble the striatum-specific SPN loss seen in HD.…”

“…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).…”

Global ribosome profiling reveals that mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein

“…Mice deleted for Htt gene, Hdh, die around embryonic day 7.5-10.5, before the full emergence of the nervous system, indicating its role in cell survival and neurogenesis (1)(2)(3)(4). Recent studies found that Htt deletion in the brain of younger mice (two months) led to death due to pancreatitis, and, in the adult brain, there was only a subtle defect in corticostriatal development and hyperactivity (5)(6)(7). The HTT gene, however, does not appear to affect development because HD human patients who are heterozygous or rare cases of homozygous for HTT appear to have normal development (8,9).…”