Amyloid pathology compresses dynamic range and degrades spatial coding in an Alzheimer's mouse model

Alzheimers disease (AD) disrupts neural circuits vital for memory and cognition. Using two-photon calcium imaging in behaving 5xFAD mice, we examined how amyloid pathology alters hippocampal CA1 activity and spatial coding. We found elevated baseline activity but reduced locomotion-driven firing, leading to a diminished neuronal dynamic range. To our knowledge, this is the first direct experimental evidence for reduced dynamic range in an AD model. These abnormalities were strongest near amyloid plaques and became more widespread with age. We also observed altered network synchrony, degraded spatial coding and increased neuronal response variability. Furthermore, place fields emerged more slowly in both familiar and novel environments, indicating impaired recall and learning. By showing a link between local plaque pathology and impaired flexible modulation of CA1 activity and progressive deficits in spatial memory coding, our study offers new insights into the circuit basis of cognitive decline in AD.