Cortical α-synuclein pathology induces cell autonomous neuronal hypoactivity and compensatory circuit changes in a model of early Lewy body dementia.

Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD) and a defining feature of Dementia with Lewy Bodies (DLB). Although many cognitive domains can be affected, impairments in visuospatial/perceptual function are relatively specific for PD and DLB compared to other dementias. Across populations, cognitive impairments correlate with the presence of α-synuclein (α-syn) pathology in limbic and neocortical brain regions. However, the specific role that α-syn pathology plays in driving cortical circuit dysfunction and cognitive impairment remains controversial. We hypothesized that inducing α-syn pathology in visual cortex in mice would impair neuronal activity and encoding of visual information, leading to visuoperceptual impairments. To test this hypothesis, we injected α-syn pre-formed fibrils (PFF) into primary visual cortex (V1) to seed endogenous α-syn pathology. Using longitudinal in vivo two-photon (2P) calcium imaging over 6 months, we recorded visually evoked activity of pyramidal cells in layer 2/3 (L2/3) and quantified α-syn pathology using C05-05, a fluorescent ligand that binds aggregated α-syn. Injection of PFFs led to the formation of sparse Lewy-like pathology in V1 and other anatomically connected regions. Measuring population activity, we found a greater percentage of neurons in PFF-injected mice were responsive to visual stimuli with lower direction selectivity compared to controls at 4-5 months post-injection (MPI). Within PFF-injected mice, neurons with large somatic Lewy-like inclusions had significantly lower visually evoked activity compared to neighboring neurons without inclusions. Conversely, the activity of neurons without somatic inclusions showed increased activity, positively correlated with the nearby burden of α-syn pathology. Measuring visuoperceptual function using a head-fixed coherent motion discrimination task, we found no impairments in visuoperceptual ability in PFF-injected mice up to 6 MPI. Our results demonstrate, for the first time in vivo, that α-syn pathology leads to cell autonomous reductions in neuronal activity and reciprocal changes in local population activity that may be compensatory, helping to preserve visuoperceptual function. Reflecting the early stages of neocortical α-syn pathology, our model provides a framework for future studies incorporating risk factors for dementia in PD to better understand the heterogeneity of cognitive symptoms and α-syn pathology across patients.