Cortical α-synuclein pathology induces neuronal hypoactivity and circuit changes but not functional impairments in a model of early Lewy body dementia

Posterior cortical impairments in visuospatial/perceptual function are common non-motor symptoms of the Lewy Body Dementias (LBD) and are relatively specific for LBDs 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 primary visual cortex (V1) in mice would impair neuronal activity and encoding of visual information, leading to visuoperceptual impairments. To test this, we injected α-syn pre-formed fibrils (PFF) into V1, causing the formation of sparse Lewy-like 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.

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). Neurons with somatic Lewy-like inclusions showed reduced activity compared to neighboring neurons without inclusions. Conversely, neurons without somatic inclusions showed increased activity, positively correlated with the local burden of α-syn pathology.

Using a coherent motion discrimination task, we found no impairments in visuoperceptual ability in PFF-injected mice. Our results demonstrate that α-syn pathology leads to reductions in neuronal activity in cells with somatic inclusions and reciprocal changes in local population activity but does not impair visuoperceptual function. Reflecting the early stages of neocortical α-syn pathology, our model provides a framework for future studies to better understand the heterogeneity of cognitive symptoms and α-syn pathology across patients.

Sravya Gadepalli for assistance with mouse breeding and colony management. Ashley Cao for assistance with mouse behavior testing. Baruc Campos, Sammy Alhassen, and Carlos Portera-Cailliau for helpful feedback, constructive criticism, and advice.

Mahmudul Hasan for his advice on microglia analysis. This work was supported by National Institutes of Health grant 1R01NS129517-01, American Parkinson’s Disease Association research grant 1178689 and Dr. Cotzias Memorial Fellowship 1268719, the UCLA Laurie and Steven C.