Striatal seeding of protofibrillar alpha-synuclein causes cortical hyperreactivity in behaving mice

Alpha-synucleinopathies are characterized by self-aggregation of the protein alpha-synuclein (a-syn), causing alterations on the molecular and cellular level. To unravel the impact of transneuronal spreading and templated misfolding of a-syn on the microcircuitry of remotely connected brain areas, we investigated cortical neuron function in awake mice 9 months after a single intrastriatal injection of a-syn preformed fibrils (PFFs), using in vivo two-photon calcium imaging. We found altered function of layer 2/3 cortical neurons in somatosensory cortex (S1) of PFF-inoculated mice, as witnessed by an enhanced response to whisking and increased synchrony, accompanied by a decrease in baseline Ca2+ levels. Stereological analyses revealed a reduction in GAD67-positive inhibitory cells in S1 in PFF-injected brains. These findings point to a disturbed excitation/inhibition balance as an important pathomechanism in alpha-synucleinopathies and demonstrate a clear association between the spread of toxic proteins and the initiation of altered neuronal function in remotely connected areas.