Weakened Intracellular Zn2+-Buffering in the Aged Dentate Gyrus and Its Involvement in Erasure of Maintained LTP

Atsushi Takeda, Haruna Tamano, Taku Murakami, Hiroyuki Nakada, Tatsuya Minamino, Yuta Koike

Memory is lost by the increased influx of extracellular Zn(2+) into neurons. It is possible that intracellular Zn(2+) dynamics is modified even at non-zincergic medial perforant pathway-dentate granule cell synapses along with aging and that vulnerability to the modification is linked to age-related cognitive decline. To examine these possibilities, vulnerability of long-term potentiation (LTP) maintenance, which underlies memory retention, to modification of synaptic Zn(2+) dynamics was compared between young and aged rats. The influx of extracellular Zn(2+) into dentate granule cells was increased in aged rats after injection of high K(+) into the dentate gyrus, but not in young rats. This increase impaired maintained LTP in aged rats. However, the impairment was rescued by co-injection of CaEDTA, an extracellular Zn(2+) chelator, or CNQX, an AMPA receptor antagonist, which suppressed the Zn(2+) influx. Maintained LTP was also impaired in aged rats after injection of ZnAF-2DA into the dentate gyrus that chelates intracellular Zn(2+), but not in young rats. Interestingly, the capacity of chelating intracellular Zn(2+) with intracellular ZnAF-2 was almost lost in the aged dentate gyrus 2 h after injection of ZnAF-2DA into the dentate gyrus, suggesting that intracellular Zn(2+)-buffering is weakened in the aged dentate gyrus, compared to the young dentate gyrus. In the dentate gyrus of aged rats, maintained LTP is more vulnerable to modification of intracellular Zn(2+) dynamics than in young rats, probably due to weakened intracellular Zn(2+)-buffering.