Distinct histological alterations of cortical interneuron types in mouse models of Huntington's disease.

Huntington's disease (HD) is a debilitating hereditary motor disorder caused by an expansion of the CAG triplet repeat in the Huntingtin gene. HD causes neurodegeneration particularly in the basal ganglia and neocortex. In the cortex, glutamatergic pyramidal neurons are known to be severely affected by the disease, but the involvement of GABAergic interneurons remains unclear. Here, we use a combination of immunostaining and genetic tracing to investigate histological changes in three major cortical interneuron types - parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) interneurons - in the R6/2 and zQ175DN mouse models of HD. In R6/2 mice, we find a selective reduction in SST and VIP, but not PV-positive cells. However, genetic labeling reveals unchanged cell numbers for all the interneuron types, pointing to molecular marker loss in the absence of cell death. We also observe a reduction in cell body size for all three interneuron populations. Furthermore, we demonstrate progressive accumulation of mutant Huntingtin (mHTT) inclusion bodies in interneurons, which occurs faster in SST and VIP compared to PV cells. In contrast to the R6/2 model, heterozygous zQ175DN knock-in HD mice do not show any significant histological changes in cortical cell types at the age of 12 months, apart from the presence of mHTT inclusions, which are abundant in pyramidal neurons and rare in interneurons. Taken together, our findings point to differential molecular changes in cortical interneuron types of HD mice.

Fluc-EGFP reporter mice reveal differential alterations of neuronal proteostasis in aging and disease.

The cellular protein quality control machinery is important for preventing protein misfolding and aggregation. Declining protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how neuronal proteostasis capacity changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc-EGFP), a conformationally unstable protein that requires chaperones for proper folding, and that reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked reaction of the Fluc-EGFP sensor in a mouse model of tauopathy, but not in mouse models of Huntington's disease. Mechanistic investigations in primary neuronal cultures demonstrate that different types of protein aggregates have distinct effects on the cellular protein quality control. Thus, Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.

Cortical circuit alterations precede motor impairments in Huntington's disease mice.

Huntington's disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to longitudinally monitor the activity of identified single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in cortical network function, with an increase in activity that affects a large fraction of cells and occurs rather abruptly within one week, preceeding the onset of motor defects. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and human HD autopsy cases reveal a reduction in perisomatic inhibitory synaptic contacts on layer 2/3 pyramidal cells. Taken together, our study provides a time-resolved description of cortical network dysfunction in behaving HD mice and points to disturbed excitation/inhibition balance as an important pathomechanism in HD.

Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space.

AIMS: Multiple sclerosis (MS) is a progressive inflammatory neurological disease affecting myelin, neurons and glia. Demyelination and neurodegeneration of cortical grey matter contribute to a more severe disease, and inflammation of the forebrain meninges associates with pathology of the underlying neocortical grey matter, particularly in deep sulci. We assessed the extent of meningeal inflammation of the cerebellum, another structure with a deeply folded anatomy, to better understand the association between subarachnoid inflammation and grey matter pathology in progressive MS. METHODS: We examined demyelinating and neuronal pathology in the context of meningeal inflammation in cerebellar tissue blocks from a cohort of 27 progressive MS cases previously characterized on the basis of the absence/presence of lymphoid-like aggregates in the forebrain meninges, in comparison with 11 non-neurological controls. RESULTS: Demyelination and meningeal inflammation of the cerebellum was greatest in those cases previously characterized as harbouring lymphoid-like structures in the forebrain regions. Meningeal inflammation was mild to moderate in cerebellar tissue blocks, and no lymphoid-like structures were seen. Quantification of meningeal macrophages, CD4+, CD8+ T lymphocytes, B cells and plasma cells revealed that the density of meningeal macrophages associated with microglial activation in the grey matter, and the extent of grey matter demyelination correlated with the density of macrophages and plasma cells in the overlying meninges, and activated microglia of the parenchyma. CONCLUSIONS: These data suggest that chronic inflammation is widespread throughout the subarachnoid space and contributes to a more severe subpial demyelinating pathology in the cerebellum.