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 α 1A -adrenergic receptor (α 1A AR) 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 α 1A AR signaling represents a promising therapeutic strategy for early AD-related cognitive dysfunction.