Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis

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.

Astrocytes in juvenile neuronal ceroid lipofuscinosis (CLN3) display metabolic and calcium signaling abnormalities

“…14 months) (Grunewald et al . ). Based on heightened Ca 2+ responses to glutamate, Cln3 Δex7/8 neurons were expected to exhibit metabolic deficits.…”

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

“…The authors proposed that CTSD is therefore an important regulator of synaptic vesicle recycling, and that its deficiency blocks this process causing neuronal dysfunction and the epilepsy prone behavior in NCL10. In another juvenile mouse model of NCL (Cln3 ∆ex1-6 ), the authors reported specific synaptic neurotransmission deficits in multiple brain areas correlating with anxiety and memory impairments [125]. Whole cell patch clamp recordings from principal neurons (PNs) in the basolateral amygdala (BLA) displayed reduced frequency of mIPSCs (miniature inhibitory postsynaptic currents) and sIPSCs (spontaneous inhibitory postsynaptic currents) as well as reduction of peak amplitude in evoked GABAergic IPSCs.…”

De‐palmitoylation by N‐(tert‐Butyl) hydroxylamine inhibits AMPAR‐mediated synaptic transmission via affecting receptor distribution in postsynaptic densities

“…Our findings reinforced the therapeutic value of NtBuHA in INCL. However, some recent findings argued against AMPAR changes in Batten disease and ascribed its synaptopathy to presynaptic changes, not aberrant levels of AMPARs 46,47. Thus, further investigations are required.…”