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

Abstract

Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20 years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional studies also demonstrated that the cerebral cortex becomes hyperexcitable with disease progression. In this review, we examine clinical and experimental evidence that cortical development is altered in HD. We also provide preliminary evidence that cortical pyramidal neurons from R6/2 mice, a model of juvenile HD, are hyperexcitable and display dysmorphic processes as early as postnatal day 7. Further, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia, which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD. Finally, we discuss recent treatments aimed at correcting abnormal brain development.

Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease

“…In this line, juvenile CX3CR1-KO mice showed increased hippocampal LTD when compared with WT, but no modifications in the adult hippocampus (Paolicelli et al, 2011). Accordingly, clinical and experimental studies suggest that mHtt-induced aberrant development is at the root of some HD functional alterations (Molero et al, 2016;Hd iPSC Consortium, 2017;Van der Plas et al, 2019), in particular cortical neurons are hyperexcitable and display dysmorphic processes (Cepeda et al, 2019). Alterations in the FKN-CX3CR1 axis could contribute to this pathological development, as this signaling system is critical for functional maturation of synapses (Hoshiko et al, 2012).…”

The Neurodevelopmental Hypothesis of Huntington’s Disease

“…To fully understand how mHTT might affect brain development, it is important to consider what the function of the normal gene (HTT) is, especially regarding brain development. At the molecular level, HTT is a multiple conformation protein that interacts with many other proteins [8] and has been reported to have different functions including spindle orientation during cell division [18], endocytosis [19], transcriptional regulation [20], establishing excitatory circuits [21], and maintenance of cell morphology [16,22]. Yet, possibly the most intriguing consideration is that of the evolutionary biologists, who have argued that triplet repeat genes enable a unique mechanism of evolution, and in particular human brain evolution [23][24][25].…”

Striatal Circuit Development and Its Alterations in Huntington’s Disease

“…As these alterations were observed in the earliest age assessed (6 years old), these findings suggest that striatal development could be impaired even earlier. In addition, this idea is in line with molecular and behavioral analyses in mouse models of HD showing early developmental deficits as well as early signs of alterations in several brain structures, including the striatum (Cepeda et al, 2019;Du et al, 2017Du et al, , 2016Molero et al, 2009).…”

“…This developmental window brings into play a host of specification, migration and interaction processes as well as numerous transcriptomic programs, all tightly regulated in time and space. An abnormal development of this architecture will subsequently have adverse consequences for proper postnatal striatal maturation, which could lead years later to the appearance of debilitating pathologies, as is the case in HD whose pathogenesis is increasingly being thought to comprise a neurodevelopmental component (Cepeda et al, 2019;Humbert, 2010;Kerschbamer and Biagioli, 2016).…”