α1A-adrenergic receptor activation ameliorates fragmented spatial exploration by improving astrocyte-neuronal coupling in the medial entorhinal cortex of Alzheimer's disease mice.

Spatial exploration is fundamental to the construction of internal cognitive maps, yet the mechanisms underlying its fine-scale microstructural disruption in Alzheimer's disease (AD) remain elusive. The medial entorhinal cortex layer II (MECII) serves as a critical hub for spatial navigation, where norepinephrine (NE) signaling modulates astrocyte activity to shape neuronal network dynamics. In this study, we combined fine-grained behavioral quantification with simultaneous in vivo dual-color fiber photometry to investigate astrocyte-neuronal coupling in the MECII of APP/PS1 transgenic mice. We report that AD mice exhibit a distinct fragmented exploration phenotype, characterized by frequent but transient sniffing and rearing bouts, which coincides with a profound loss of temporal synchronization between MECII astrocytes and neurons. Notably, pharmacological activation of the noradrenergic axis using the highly selective α1A-adrenergic receptor (α1AAR) agonist A61603 successfully re-established astrocyte-neuronal network coupling across behavioral states. This intervention significantly ameliorated the fragmented exploration phenotype without altering general locomotor activity. These findings identify disrupted astrocyte-neuronal temporal coordination in the MECII as a pivotal physiological mechanism driving spatial exploration deficits in AD, suggesting that restoring α1AAR signaling represents a promising therapeutic strategy for early AD-related cognitive dysfunction.