Abstract
Juvenile Batten disease is the most common progressive neurodegenerative disorder of childhood. It is associated with mutations in the CLN3 gene, causing loss of function of CLN3 protein and degeneration of cerebellar and retinal neurons. It has been proposed that changes in granule cell AMPA-type glutamate receptors (AMPARs) contribute to the cerebellar dysfunction. In this study we compared AMPAR properties and synaptic transmission in cerebellar granule cells from wild-type and Cln3 knockout mice. In Cln3Δex1–6 cells the amplitude of AMPA-evoked whole-cell currents was unchanged. Similarly, we found no change in the amplitude, kinetics, or rectification of synaptic currents evoked by individual quanta, or in their underlying single-channel conductance. We found no change in cerebellar expression of GluA2 or GluA4 protein. By contrast, we observed a reduced number of quantal events following mossy-fiber stimulation in Sr2+, altered short-term plasticity in conditions of reduced extracellular Ca2+, and reduced mossy fiber vesicle number. Thus, while our results suggest early presynaptic changes in the Cln3Δex1–6 mouse model of juvenile Batten disease, they reveal no evidence for altered postsynaptic AMPARs.
Significance Statement Juvenile Batten disease is an inherited lysosomal storage disorder that affects children and leads to premature death. Caused by mutations in the CLN3 gene, it results in a loss of CLN3 protein and neuronal degeneration. It has been proposed that changes in granule cell AMPA-type glutamate receptors contribute to cerebellar dysfunction. Here, we show that the properties of postsynaptic AMPA receptors in granule cells from juvenile Cln3Δex1–6 mice are unaltered. Instead, loss of CLN3 protein leads to early presynaptic changes and altered short-term plasticity.
Footnotes
Authors report no conflict of interest.
This work was supported by the MRC (MR/J002976/1 to SGC-C and MF; MR/J012998/1 to MF and SGCC) and the Wellcome Trust (086185/Z/08/Z to SGC-C and MF). ELN was in receipt of a BBSRC studentship (BB/D526961/1).
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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