DORSAL STRIATAL GLYCINERGIC DYSFUNCTION AND NEURONAL EXCITABILITY ALTERATIONS IN EARLY ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is the leading cause of dementia worldwide and is characterized by progressive cognitive and non-cognitive impairments. In addition to cortical pathology, increasing evidence indicates that AD is associated with alterations in subcortical regions, including the striatum, together with changes in motor activity and motivated behavior. The striatum is subdivided into ventral and dorsal regions, with the dorsal striatum (DS) serving as the primary input nucleus of the basal ganglia and playing a vital role in regulating movement, goal-directed behavior, and motor learning. The DS can be categorized into dopamine D1 receptor (D1R)- and D2 receptor (D2R)-expressing striatal projection neurons (SPNs). The glycine receptor alpha2 subunit (GlyRα2) is the predominant functional subunit in the DS and modulates SPN activity by inhibiting dopamine-stimulated D1 receptor–expressing neurons. The aim of this study is to investigate molecular, cellular, and physiological alterations in the dorsal striatum using 6-month-old APP/PS1 transgenic mice (early AD model) and to determine their impact on neuronal excitability and striatal function. Immunohistochemical analyses in AD mice show alterations in the dorsal striatum characterized by reduced GlyRα2 expression and exacerbated striatal excitability. In addition, AD mice exhibit increased chocolate-conditioned behavior, consistent with enhanced motivational drive. Together, these findings suggest that dysregulation of glycinergic signaling in the DS may contribute to altered striatal function associated with motor and motivational disturbances in AD.
Acknowledgement: Fondecyt 11251074