Age-dependent alterations in neuronal activity in the hippocampus and visual cortex in a mouse model of Juvenile Neuronal Ceroid Lipofuscinosis (CLN3)

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

“…We recently reported that neuronal activity was exaggerated in the hippocampus and cortex of Cln3 Δex7/8 mice between 1 and 4 months of age (Burkovetskaya et al . ), supporting the heightened neuronal responses presented here. A recent report also described neuronal perturbations in Cln3 ‐deficient mice, but this was only examined at late stage disease (i.e.…”

Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder

“…Our VSDI findings of altered excitability in 2-month-old CLN3 -/hippocampal slices suggest that lysosomal defects can disrupt CNS function well before cell death occurs (10,11,23). Increased axonal excitability has been reported previously in very early-stage CLN3 Δex7/8 mice (16). Early changes in intrinsic or synaptic properties of CLN3 -/neurons and/or glia may establish abnormal electrical networks that cannot be corrected through reversal of the lysosomal defect alone.…”

“…The hippocampus appears to be particularly vulnerable to disease with relatively early pathologic changes (10)(11)(12)(13)(14). Consistent with this, CLN3 patients suffer from progressive memory impairment, and 1 mouse model demonstrates deficits in hippocampal-mediated learning and memory (11,15), along with functional defects in specific hippocampal cell types in late-stage disease (11,16).…”

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

“…Furthermore, dysfunctional CLN3 may lead to deficits in spine morphology and to a reduced number of active synapses ( Golabek et al, 2000 ; Esteves da Silva et al, 2015 ; Padamsey et al, 2017 ). In addition, age-dependent changes in axonal excitability have been described in the Cln3 Δex7/8 mouse model ( Burkovetskaya et al, 2017 ). Different from our study, synaptic transmission was not evaluated directly by single-cell recordings in this study.…”

“…How these molecular changes induce the neurological symptoms of the JNCL is still unknown. Recent studies using extracellular field potential recordings showed that axonal excitability is altered in the hippocampal CA1-region and the visual cortex of the Cln3 Δex7/8 mouse model ( Burkovetskaya et al, 2017 ). It is speculated that early changes in the balance of glutamate and GABA may contribute to seizure development and neurodegeneration, as neurons in Cln3 Δex1-6 mice seem to be exceptionally vulnerable to glutamate excitotoxicity ( Pears et al, 2005 ; Finn et al, 2011 ; Kovács et al, 2006 ).…”