Heterosynaptic metaplasticity in the hippocampus in vivo: A BCM-like modifiable threshold for LTP

The homeostatic maintenance of the "modification threshold" for inducing lo ng-term potentiation (LTP) is a fundamental feature of the Bienenstock, Coo per, and Munro (BCM) model of synaptic plasticity. In the present study, tw o key features of the modification threshold, its heterosynaptic expression and its regulation by postsynaptic neural activity, were tested experiment ally in the dentate gyrus of awake, freely moving rats. Conditioning stimul ation ranging from 10 to 1,440 brief 400-Hz trains, when applied to medial perforant path afferents, raised the threshold for LTP induction heterosyna ptically in the neighboring lateral perforant path synapses. This effect re covered slowly over a 7- to 35-day period. The same conditioning paradigms, however, did not affect the reversal of long-term depression. The inhibiti on of LTP by medial-path conditioning stimulation was N-methyl-D-aspartate (NMDA) receptor-dependent, but antidromic stimulation of the granule cells could also inhibit lateral path LTP induction, independently of NMDA recept or activation. Increased calcium buffering is a potential mechanism underly ing the altered LTP threshold, but the levels of two important calcium-bind ing proteins did not increase after conditioning stimulation, nor was de no vo protein synthesis required for generating the threshold shift. These dat a confirm, in an in vivo model, two key postulates of the BCM model regardi ng the LTP threshold. They also provide further evidence for the broad sens itivity of synaptic plasticity mechanisms to the history of prior activity, i.e., metaplasticity.