Abstract
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3Δex1-6) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.
Highlights
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) is the most prevalent inherited neurodegenerative disease in childhood caused by autosomal recessive loss-of-function mutations in the CLN3 gene
We found that synaptic transmission is severely disturbed in the amygdala, hippocampus, and cerebellum accounting for progressive disease signs in the Cln3Dex1-6 mouse model
Synaptic transmission defects in the amygdala are associated with anxiety related behavior in Cln3Dex1-6 mice
Summary
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) is the most prevalent inherited neurodegenerative disease in childhood caused by autosomal recessive loss-of-function mutations in the CLN3 gene. The clinical syndrome consists of gradual visual loss, motor and cognitive decline, ataxia, seizures, psychiatric abnormalities, and death in the third or fourth decade of life (Jalanko and Braulke, 2009; Adams et al, 2007; Haltia and Goebel, 2013). The CLN3 protein is a transmembrane protein (Ratajczak et al, 2014) localized in synapses, in early endosomes (UusiRauva et al, 2012), and in the Golgi apparatus (Getty et al, 2013). Mutations in the CLN3 gene and its homologues have been analyzed in various species including mice, Drosophila, and yeast, revealing multiple biochemical defects and interactions at the cellular level
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