Aberrant medial entorhinal cortex dynamics link tau pathology to spatial memory impairment

Area of Science:

• Neuroscience
• Neurodegenerative Diseases
• Molecular Biology

Background:

• Early Alzheimer's disease (AD) is characterized by spatial memory deficits and tau pathology in the entorhinal cortex (EC).
• The precise contribution of EC neural activity to memory impairment in tauopathy remains largely unknown.

Purpose of the Study:

• To investigate medial EC (MEC) neural activity during spatial learning in a mouse model of tauopathy.
• To correlate MEC neuronal dysfunction with spatial memory deficits and tau accumulation.

Main Methods:

• Utilized in vivo two-photon calcium imaging combined with virtual reality.
• Examined MEC activity in PS19 tauopathy mice during a 10-day spatial learning task.
• Quantified tau phosphorylation in different MEC cell types.

Main Results:

• PS19 mice displayed significant learning deficits and impaired MEC neuron function, including disrupted speed modulation and spatial encoding.
• Pyramidal cells, with higher tau accumulation, showed more pronounced deficits than stellate cells, especially in males.
• MEC activity, particularly from non-grid and pyramidal cells, accurately predicted learning performance and differentiated PS19 from wild-type mice.

Conclusions:

• Medial EC (MEC) dysfunction is a key neural correlate of spatial memory decline in Alzheimer's disease-related tauopathy.
• Specific deficits in MEC neuronal activity, linked to tau accumulation, underlie memory impairment.
• Findings suggest potential diagnostic and therapeutic targets within the MEC for AD.