Details

Autor(en) / Beteiligte

• Koch, Sabine
• Molchanova, Svetlana M
• Wright, Ann K
• Edwards, Andrew
• Cooper, Jonathan D
• Taira, Tomi
• Gillingwater, Thomas H
• Tyynelä, Jaana

Titel

Morphologic and Functional Correlates of Synaptic Pathology in the Cathepsin D Knockout Mouse Model of Congenital Neuronal Ceroid Lipofuscinosis

Ist Teil von

• Journal of neuropathology and experimental neurology, 2011-12, Vol.70 (12), p.1089-1096

Ort / Verlag

Hagerstown, MD: American Association of Neuropathologists, Inc

Erscheinungsjahr

2011

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• ABSTRACTMutations in the cathepsin D (CTSD) gene cause an aggressive neurodegenerative disease (congenital neuronal ceroid lipofuscinosis) that leads to early death. Recent evidence suggests that presynaptic abnormalities play a major role in the pathogenesis of CTSD deficiencies. To identify the early events that lead to synaptic alterations, we investigated synaptic ultrastructure and function in presymptomatic CTSD knockout (Ctsd) mice. Electron microscopy revealed that there were significantly greater numbers of readily releasable synaptic vesicles present in Ctsd mice than in wild-type control mice as early as postnatal day 16. The size of this synaptic vesicle pool continued to increase with disease progression in the hippocampus and thalamus of the Ctsd mice. Electrophysiology revealed a markedly decreased frequency of miniature excitatory postsynaptic currents (mEPSCs) with no effect on paired-pulse modulation of the evoked excitatory post synaptic potentials in the hippocampus of Ctsd mice. The reduced mEPSCs frequency was observed before the appearance of epilepsy or any morphologic sign of synaptic degeneration. Taken together, these data indicate that CTSD is required for normal synaptic function and that a failure in synaptic trafficking or recycling may bean early and important pathologic mechanism in Ctsd mice; thesepresynaptic abnormalities may initiate synaptic degeneration in advance of subsequent neuronal loss.