Kurzfassung

Juvenile Neuronal Ceroid-Lipofuscinosis is caused by mutations in the CLN3 gen. Hallmarks of the disease are visual deterioration, cognitive decline, seizures and motor deficits. Growing evidence point to a role of CLN3 in lysosomal and endosomal function while it stays elusive how loss of function of CLN3 causes neuronal dysfunction and subsequently neurodegeneration. We hypothesize that CLN3-deficiency impairs basic neuronal properties and synaptic transmission resulting in...Juvenile Neuronal Ceroid-Lipofuscinosis is caused by mutations in the CLN3 gen. Hallmarks of the disease are visual deterioration, cognitive decline, seizures and motor deficits. Growing evidence point to a role of CLN3 in lysosomal and endosomal function while it stays elusive how loss of function of CLN3 causes neuronal dysfunction and subsequently neurodegeneration. We hypothesize that CLN3-deficiency impairs basic neuronal properties and synaptic transmission resulting in abnormal neuronal and network activity and a detrimental shift in excitatory-inhibitory balance, which ultimately leads to neurodegeneration[MO1] .
Therefore, we will study neuronal and synaptic deficits in the hippocampus and the lateral geniculate nucleus (LGN) of Cln3Δex7/8-mice at different ages to determine the time point of early pathologies caused by Cln3                                                       deficiency. To investigate E/I balance, pre- and postsynaptic deficits and changes in synaptic and structural plasticity, we will analyses intrinsic properties, synaptic transmission and plasticity, extrasynaptic receptor function and morphology of LGN and hippocampal neurons. In-vivo recordings of the spiking of hippocampal neurons in freely moving mice and of the lateral geniculate nucleus in head-fixed mice in response to visual stimuli will allow us to determine early changes in neuronal and network activity. Furthermore, we will test if rAAV-mediated neuron-specific expression of cln3 in Cln3Δex7/8-mice prevents neuronal deficits. This will allow us to address if neuronal cln3-deficiency causes the observed defects.
This study will shed light on mechanisms of early neuronal dysfunction paving the way for new treatment approaches. In addition, the anticipated neuronal defects could be valuable biomarkers for the assessment of preclinical animal studies as they can be tested with high specificity and sensitivity. This will foster the development of novel treatment strategies.
 [MO1]????» weiterlesen» einklappen