Cortical circuit dysfunction in a mouse model of alpha-synucleinopathy in vivo

Blumenstock, Sonja; Sun, Fanfan; Klaus, Carolin; Marinkovic, Petar; Sgobio, Carmelo; Paeger, Lars; Liebscher, Sabine und Herms, Jochen (2021): Cortical circuit dysfunction in a mouse model of alpha-synucleinopathy in vivo. In: Brain Communications, Bd. 3, Nr. 4, fcab273

Abstract

Blumenstock et al. report brain state-dependent hyperreactivity in somatosensory cortex months after striatal seeding of alpha-synuclein preformed fibrils. A concerted reduction of GAD67 positive interneurons argues for excitation/inhibition imbalance as a driver of cortical network dysfunction. Considerable fluctuations in cognitive performance and eventual dementia are an important characteristic of alpha-synucleinopathies, such as Parkinson's disease and Lewy Body dementia and are linked to cortical dysfunction. The presence of misfolded and aggregated alpha-synuclein in the cerebral cortex of patients has been suggested to play a crucial role in this process. However, the consequences of a-synuclein accumulation on the function of cortical networks at cellular resolution in vivo are largely unknown. Here, we induced robust a-synuclein pathology in the cerebral cortex using the striatal seeding model in wild-type mice. Nine months after a single intrastriatal injection of a-synuclein preformed fibrils, we observed profound alterations of the function of layer 2/3 cortical neurons in somatosensory cortex by in vivo two-photon calcium imaging in awake mice. We detected increased spontaneous activity levels, an enhanced response to whisking and increased synchrony. Stereological analyses revealed a reduction in glutamic acid decarboxylase 67-positive inhibitory neurons in the somatosensory cortex of mice injected with preformed fibrils. Importantly, these findings point to a disturbed excitation/inhibition balance as a relevant driver of circuit dysfunction, potentially underlying cognitive changes in alpha-synucleinopathies.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198