Mixed Neurodevelopmental and Neurodegenerative Pathology inNhe6-Null Mouse Model of Christianson Syndrome

Abstract

Christianson syndrome (CS) is an X-linked disorder resulting from loss-of-function mutations in SLC9A6, which encodes the endosomal Na+/H+ exchanger 6 (NHE6). Symptoms include early developmental delay, seizures, intellectual disability, nonverbal status, autistic features, postnatal microcephaly, and progressive ataxia. Neuronal development is impaired in CS, involving defects in neuronal arborization and synaptogenesis, likely underlying diminished brain growth postnatally. In addition to neurodevelopmental defects, some reports have supported neurodegenerative pathology in CS with age. The objective of this study was to determine the nature of progressive changes in the postnatal brain in Nhe6-null mice. We examined the trajectories of brain growth and atrophy in mutant mice from birth until very old age (2 yr). We report trajectories of volume changes in the mutant that likely reflect both brain undergrowth as well as tissue loss. Reductions in volume are first apparent at 2 mo, particularly in the cerebellum, which demonstrates progressive loss of Purkinje cells (PCs). We report PC loss in two distinct Nhe6-null mouse models. More widespread reductions in tissue volumes, namely, in the hippocampus, striatum, and cortex, become apparent after 2 mo, largely reflecting delays in growth with more limited tissue losses with aging. Also, we identify pronounced glial responses, particularly in major fiber tracts such as the corpus callosum, where the density of activated astrocytes and microglia are substantially increased. The prominence of the glial response in axonal tracts suggests a primary axonopathy. Importantly, therefore, our data support both neurodevelopmental and degenerative mechanisms in the pathobiology of CS.

Complex Neurological Phenotype in Female Carriers of <b><i>NHE6</i></b> Mutations

“…Postmortem examination of 2 CS males in their 40s and 50s found widespread neuronal and glial loss, as well as accumulation of tau-positive tangle-like inclusions [9]. Furthermore, neurodegenerative features have been reported in an Nhe6 -null mouse model such as loss of Purkinje cells in the cerebellum, loss of tissues and synapses, and a strong microglial response [10]. …”

Assorted dysfunctions of endosomal alkali cation/proton exchanger SLC9A6 variants linked to Christianson syndrome

“…Less severe neuronal loss and gliosis have been documented in other brain regions, such as the cerebral cortex and hippocampus (6). Similar degeneration of the cerebellum and mild undergrowth and atrophy of the hippocampus, striatum, and cortex were also observed in Slc9a6 knockout mice (32,34,35). The variable penetrance and seemingly selective deterioration of certain neuronal populations upon loss of NHE6 function, despite its broad expression throughout the CNS, is not well understood but may reflect the nature of the mutation as well as other ill-defined genetic-modifier effects or compensatory mechanisms.…”

“…Previous studies have revealed that genetic disruption of NHE6 expression causes degeneration of a subset of neurons within the cortex, hippocampus and especially the cerebellum which exhibits extensive Purkinje cell loss with age (32,34,35). Neurons in other brain regions, despite the loss of NHE6 expression, do not appear as severely affected.…”

“…Female carriers exhibit variable penetrance and milder symptoms (1,21,22,31). A CS-like phenotype is also reiterated in Slc9a6/Nhe6 knockout (KO) male mice (Nhe6 −/Y ), including atrophy and degeneration of cortical, hippocampal and especially cerebellar Purkinje neurons that parallel deficits in visuospatial memory and motor dexterity, and increased mortality prior to weaning (32)(33)(34). Likewise, heterozygous Nhe6 KO female mice (Nhe6 −/+ ) display a comparable, albeit milder, range of symptoms (35).…”

The Amyloid Clearance Defect in ApoE4 Astrocytes is Corrected by Epigenetic Restoration of NHE6

“…Consistent with a role in amyloid pathology, in vivo Aβ levels were found to be significantly higher in the brains of NHE6 KO mice. These findings could have implications for Christianson 5 syndrome patients who have loss of function mutations in NHE6 and exhibit agedependent hallmarks of neurodegeneration 17, 18 . In summary, we identify NHE6 as a novel ApoE effector and suggest potential therapeutic options in the treatment of amyloid disorders.…”