Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis

Abstract

Infantile neuronal ceroid lipofuscinosis (INCL) is caused by deficiency of the lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1). We have investigated the onset and progression of pathological changes in Ppt1-deficient mice (Ppt1 −/− ) and the development of their seizure phenotype. Surprisingly, cortical atrophy and neuron loss occurred only late in disease progression, but were preceded by localized astrocytosis within individual thalamic nuclei and the progressive loss of thalamic neurons that relay different sensory modalities to the cortex. This thalamic neuron loss occurred first within the visual system and only subsequently in auditory and somatosensory relay nuclei or the inhibitory reticular thalamic nucleus. The loss of granule neurons and GABAergic interneurons followed in each corresponding cortical region, before the onset of seizure activity. These findings provide novel evidence for successive neuron loss within the thalamus and cortex in Ppt1 −/− mice, revealing the thalamus as an important early focus of INCL pathogenesis.

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression

“…As a positive control, brains were taken from Ppt1 À/À mice that display intense microglial activation as part of their pathological neuronal ceroid lipofuscinosis phenotype. 13 As previously reported, 13 the motor cortex of Ppt1 À/À mice revealed intense CD68 immunoreactivity (Figure 5a), but there was no obvious increase in staining for this marker of microglial activation in the brains injected with any of the viruses (Figures 5c --f), compared with uninjected brains (Figure 5b). Higher-power examination of the M1 motor cortex revealed microglia in a quiescent state in uninjected and vectoradministered brains compared with activated and swollen microglia in the Ppt1 À/À brains (inset boxes).…”

“…The expression of GFP and CD68 was measured by quantitative thresholding image analysis as previously described 13,48 with each antigen analysed blind to the type of vector injected. Briefly, 40 non-overlapping RGB images were captured across four consecutive sections through the CA1 subfield of the hippocampus, caudate putamen, motor and piriform cortex, medial septum, VPM/VPL region of the thalamus and the cerebellar nodule.…”

Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors

“…These estimates were performed as described previously. [26][27][28] In brief, a random starting section was chosen, followed by every sixth GFP-stained section thereafter. GFP-expressing cells were sampled using a series of counting frames distributed according to a grid superimposed onto the section.…”

Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis

“…Although NCL mouse models have shown many similar pathological characteristic as patients Seigel et al, 2002;Sappington et al, 2003;Pontikis et al, 2004;Pontikis et al, 2005;Kielar et al, 2007), neuroanatomical analysis of the Cln3 -/-mice has failed to reveal any regional volumetric changes of the striatum, although detailed analysis of target cell loss in this area has not been performed (Pontikis et al, 2004). Interestingly, in the Cln3 -/-mice, as well as other NCL models, there is a marked increase in the levels of both reactive astrocytes and microglia within this compartment, indicative of cellular damage (Pontikis et al, 2004;Pontikis et al, 2005;Kielar et al, 2007). Interestingly, gene expression studies of the Cln3 -/-mouse brain have uncovered a marked decrease in the expression of catechol-O-methyl transferase (COMT) (Elshatory et al, 2003).…”