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

- This report is the first to examine neuronal activity in the Cln3Δex7/8 HPC and VC using electrophysiological approaches.
- Axonal excitability was altered in Cln3Δex7/8 HPC and VC neurons, with changes in synaptic strength of CA1 HPC neurons.
- Short-term plasticity was reduced in Cln3Δex7/8 HPC and VC neurons throughout disease development (1-12 months of age).
- Electrophysiological recordings suggest that intrinsic non-synaptic short-term plasticity is most affected by CLN3 mutation.
- Cln3Δex7/8 neuronal dysfunction is evident at 1 month of age, which significantly precedes neuronal loss at 12-18 months.

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a fatal lysosomal storage disease caused by autosomal recessive mutations in CLN3. JNCL is typified by progressive neurodegeneration that has been suggested to occur from excessive excitatory and impaired inhibitory synaptic input; however, no studies to date have directly evaluated neuronal function. To examine changes in neuronal activity with advancing disease, electrophysiological recordings were performed in the CA1 hippocampus (HPC) and visual cortex (VC) of acute brain slices from Cln3Δex7/8 mice at 1, 4, 8, and 12 months of age. Basic electrophysiological parameters, such as field excitatory post-synaptic potential (fePSP) and population spike (PS) amplitudes, were not altered in Cln3Δex7/8 CA1 and VC neurons at any age. However, fiber volley (FV) amplitudes were significantly increased in Cln3Δex7/8 neurons in the HPC at 1 month as well as layer II/III of the VC at 1 and 4 months, suggesting increased axonal excitability. In older Cln3Δex7/8 mice (8 and 12 months), FV amplitude in the CA1 HPC and VC reached levels that were equal to or significantly lower than WT animals. Significant alterations in the synaptic strength of Cln3Δex7/8 CA1 neurons were also linked to age-dependent changes in axonal responses. Additionally, paired-pulse and 12-pulse facilitation responses calculated from PS recordings were significantly decreased in the CA1 HPC and layer II/III of the VC of Cln3Δex7/8 mice at all ages, suggesting permanent alterations in neuronal short-term plasticity. Collectively, our study has identified novel age- and region-dependent alterations in axonal excitability as well as synaptic and non-synaptic neuronal activity in Cln3Δex7/8 mice during disease progression, which may inform neurodegenerative mechanisms in JNCL.