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bioRxiv · 10.1101/2025.07.31.668024

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

Theint, A. T.·Cazares, N.·Zhang, S.·Zhang, N.·Mosley, R.·Higuchi, M.·Peng, C.·Zeiger, W. A.
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Abstract

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 -synuclein (-syn) pathology in limbic and neocortical brain regions. However, the specific role that -syn pathology plays in driving cortical circuit dysfunction and cognitive impairment remains controversial. We hypothesized that inducing -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 -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 -syn pathology using C05-05, a fluorescent ligand that binds aggregated -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 -syn pathology. Using a coherent motion discrimination task, we found no impairments in visuoperceptual ability in PFF-injected mice. Our results demonstrate that -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 -syn pathology, our model provides a framework for future studies to better understand the heterogeneity of cognitive symptoms and -syn pathology across patients.

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Theint, A. T., Cazares, N., Zhang, S., Zhang, N., Mosley, R., Higuchi, M., Peng, C., Zeiger, W. A.. 2025-08-01. Cortical α-synuclein pathology induces cell autonomous neuronal hypoactivity and compensatory circuit changes in a model of early Lewy Body Dementia. https://doi.org/10.1101/2025.07.31.668024

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