Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons.

Infantile Neuronal Ceroid Lipofuscinosis (INCL) results from mutations in the palmitoyl protein thioesterase (PPT1, CLN1) gene and is characterized by dramatic death of cortical neurons. We generated Ppt1Deltaex4 mice by a targeted deletion of exon 4 of the mouse Ppt1 gene. Similar to the clinical phenotype, the homozygous mutants show loss of vision from the age of 8 weeks, seizures after 4 months and paralysis of hind limbs at the age of 5 months. Autopsy revealed a dramatic loss of brain mass and histopathology demonstrated accumulation of autofluorescent granular osmiophilic deposits (GRODS), both characteristic of INCL. At 6 months, the homozygous Ppt1Deltaex4 mice showed a prominent loss of GABAergic interneurons in several brain areas. The transcript profiles of wild-type and mutant mouse brains revealed that most prominent alterations involved parts of the immune response, implicating alterations similar to those of the aging brain and neurodegeneration. These findings make the Ppt1Deltaex4 mouse an interesting model for the inflammation-associated death of interneurons.