title: Age-dependent alterations in neuronal activity in the hippocampus and visual cortex in a mouse model of Juvenile Neuronal Ceroid Lipofuscinosis (CLN3).
abstract: 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 Cln3Δex7/8mice at 1, 4, 8, and 12months of age. Basic electrophysiological parameters, such as field excitatory post-synaptic potential (fePSP) and population spike (PS) amplitudes, were not altered in Cln3Δex7/8CA1 and VC neurons at any age. However, fiber volley (FV) amplitudes were significantly increased in Cln3Δex7/8neurons in the HPC at 1month as well as layer II/III of the VC at 1 and 4months, suggesting increased axonal excitability. In older Cln3Δex7/8mice (8 and 12months), 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 Cln3Δex7/8CA1 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 Cln3Δex7/8mice 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 Cln3Δex7/8mice during disease progression, which may inform neurodegenerative mechanisms in JNCL.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Burkovetskaya
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Karpuk
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: tkielian@unmc.edu.
authors.forename: Tammy
authors.initials: T
authors.lastname: Kielian
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism / Q000503:physiopathology; D014793:Visual Cortex / Q000503:physiopathology*
chemical_list: D008562:Membrane Glycoproteins; D018832:Molecular Chaperones
keywords: Axonal activity; CLN3; Electrophysiology; Fiber volley; Field potential; Hippocampus; Juvenile Batten disease; Neocortex; Neuron; Short-term plasticity