Developmental impairments neurotransmitter systems in Cln3Δex7/8 knock-in mice, an animal model of juvenile neuronal ceroid lipofuscinosis

The neuronal ceroidlipofuscinoses (NCL) are a group of neurodegenerative disorders and are the most common lysosomal storage diseases of infancy and childhood. Juvenile NCL is caused by CLN3 mutation, producing retinal degeneration, uncontrollable seizures, cognitive and motor decline, and early death before the age of 30 years. To study the pathogenetic mechanisms of the disease, Cln3 knock-in mice (Cln3(Delta ex-7/8)) have been generated, which reproduce the 1.02-kb deletion in the CLN3 gene observed in more than 85% of juvenile NCL patients. To characterize the impact of the common Cln3 mutation on development of auto-fluorescent storage material, gliosis, glucose metabolism, oxidative stress, and transmitter receptors during postnatal brain maturation, brain tissue of Cln3(Delta ex7/8) mice at the ages of 3, 4, 5, 6, 9, and 19 months was subjected to immunocytochemistry to label gliotic markers and nitric oxide synthases; photometric assays to assess enzyme activities of glycolysis and antioxidative defense systems; and level of reactive nitrogen species as well as quantitative receptor autoradiography to detect select cholinergic, glutamatergic, and GABAergic receptor subtypes. The developmental increase in cerebral cortical autofluorescent lipofuscin-like deposition is accompanied by a significant astro- and microgliosis, increased activities of lactate dehydrogenase and phosphofructokinase, decreased level of glutathione peroxidase, enhanced amount of reactive nitrogen species, and lowered binding levels of N-methyl-D-aspartate- and M1-muscarinic acetylcholine receptors in select brain regions but hardly in GABA(A) receptor sites compared with wild-type mice. Detailed elucidation of the sequence of pathological events during postnatal development highlights new potential strategies for symptomatic treatment of the disease. (c) 2008 Wiley-Liss, Inc.