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

Abstract

The homeostatic maintenance of the ''modification threshold'' for inducing long-term potentiation (LTP) is a fundamental feature of the Bienenstock, Cooper, and Munro (BCM) model of synaptic plasticity. In the present study, two key features of the modification threshold, its heterosynaptic expression and its regulation by postsynaptic neural activity, were tested experimentally in the dentate gyrus of awake, freely moving rats. Conditioning stimulation ranging from 10 to 1,440 brief 400-Hz trains, when applied to medial perforant path afferents, raised the threshold for LTP induction heterosynaptically in the neighboring lateral perforant path synapses. This effect recovered slowly over a 7-to 35-day period. The same conditioning paradigms, however, did not affect the reversal of long-term depression. The inhibition 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 receptor activation. Increased calcium buffering is a potential mechanism underlying the altered LTP threshold, but the levels of two important calcium-binding proteins did not increase after conditioning stimulation, nor was de novo protein synthesis required for generating the threshold shift. These data confirm, in an in vivo model, two key postulates of the BCM model regarding the LTP threshold. They also provide further evidence for the broad sensitivity of synaptic plasticity mechanisms to the history of prior activity, i.e., metaplasticity.M any experimental observations now support the suggestion that long-term potentiation (LTP) and long-term depression (LTD) underlie not only long-term information storage important for learning and memory but also the experiencedependent adaptations important for tuning the patterns of synaptic connectivity in the developing nervous system (1, 2). However, for these mechanisms to store information optimally, regulatory processes must exist to maintain the modifiable synapses of the network within a useful dynamic range. One proposal to account for such homeostatic regulation was made by Bienenstock, Cooper, and Munro (BCM; ref. 3) in their model of visual cortical receptive field plasticity during development. These authors suggested that the ''modification threshold'' (the level of postsynaptic response below which gives LTD and above which gives LTP) is itself dynamically regulated by the average level of postsynaptic activity. For example, if visual cortical neurons suffered a prolonged reduction in their activity because of visual deprivation, then the modification threshold would be correspondingly reduced. This adaptive response allows the preservation of a broad range of LTP and LTD responses despite treatments that restrict the firing repertoire of those neurons. A converse process, involving an elevated modification threshold, occurs if a neuron's level of activity is increased over a prolonged period. The term ''metaplasticity'' has ...

Hippocampal Synaptic Metaplasticity Requires Inhibitory Autophosphorylation of Ca2+/Calmodulin-Dependent Kinase II

“…2 B 1 ,C)]. These data are in good agreement with published data, in which priming applied to the medial perforant path in vivo raised the threshold for induction of lateral perforant path LTP (Abraham et al, 2001). These findings indicate that heterosynaptic metaplasticity at these pathways is a robust phenomenon present both in vivo and in vitro.…”

Metaplastic Regulation of Long-Term Potentiation/Long-Term Depression Threshold by Activity-Dependent Changes of NR2A/NR2B Ratio

“…In addition, the metaplasticity that we observed here is homosynaptic in nature. It still remains to be determined whether the activity at the CA1 neurons that we studied could also induce the same affect on subsequent plasticity at neighboring synapses, as is predicted by the BCM theory and supported by recent studies (Holland and Wagner, 1998;Wang and Wagner, 1999;Abraham et al, 2001;Roth-Alpermann et al, 2006).…”

Mechanisms of heterosynaptic metaplasticity

“…Overall, the BCM theory has been hugely influential in the plasticity field by formalizing testable predictions not only about the direction and degree of plasticity arising from conjunctive pre-and postsynaptic activity, but also about the activitydependent regulation of the LTP threshold. These predictions have been confirmed, at least in part, by studies in the visual cortex and hippocampus [6][7][8][9][10].…”