Effects of age and dopamine D2L receptor-deficiency on motor and learning functions.

Decreases in the activity or density of dopamine D2 receptor (D2R) have been associated with age-related changes and neurodegenerative diseases such as Parkinson's disease. There are two isoforms of the D2R, termed the D2 long receptor (D2LR) and D2 short receptor (D2SR). To study the function of these two isoforms and their role in aging, we generated mice selectively lacking D2LR (D2L-/-). Here, we showed that middle-aged (12 months) to aged wild-type (WT) mice (22-24 months) displayed significantly lower levels of motor and learning functions than young WT mice (3 months). Interestingly, young D2L-/- mice (which still express D2SR) showed behavioral deficits similar to aged WT mice. It is possible that deletion of the D2LR might facilitate the aging process in mice. Our results also suggest that a deterioration of the D2LR (but not D2SR) system during aging may account, at least in part, for the motor and learning deficits exhibited in aged WT mice. We also showed that the critical age at which significant reduction in behavior occurred varied among different behaviors. Defining the age-related critical periods and understanding the role of the two D2R isoforms in aging may facilitate the development of new strategies for delaying or ameliorating age-related motor and learning impairments.