Interactions between Hebbian and Homeostatic Synaptic Plasticity in Hippocampal Circuits.

摘要

Hebbian forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), are thought to underlie learning and memory, but these processes may have a destabilizing effect on neural activity. Homeostatic synaptic plasticity (HSP), often studied as compensatory adaptations driven by perturbations of neuronal activity, is thought to counteract the destabilizing influence of Hebbian plasticity in neural circuits. However, it is unclear how these opposing forces on synaptic efficacy co-exist in neuronal circuits, largely because of the differing preparations and time domains over which they are studied. To investigate interactions between these distinct forms of synaptic plasticity, we characterized a rapid form of HSP expressed at CA3-CA1 synapses in acute hippocampal slices. By altering the frequency of Schaffer collateral stimulation, we induced compensatory changes in synaptic strength that are bidirectional, input-specific and mechanistically distinct from LTP and LTD. These features allowed us to address the manner by which HSP interacts with Hebbian plasticity at the same population of synapses. Our results reveal that input-specific HSP generally offsets the magnitude of subsequent Hebbian plasticity expression in an additive fashion. Strikingly, we found that prior induction of Hebbian plasticity constrained the magnitude of subsequent HSP expression. This interaction only occurs if both plasticities alter synaptic strength in the same direction, as input-specific HSP was otherwise able to compete with previously established Hebbian plasticity. We identify a scenario in which neither form of plasticity studied is dependent on new protein synthesis, yet the metaplastic interaction between them is mediated by local protein synthesis. Taken together, the magnitude and durability of synaptic efficacy changes are a product of both Hebbian and homeostatic mechanisms, suggesting that HSP may also influence information coding and storage in neural circuits. Finally, we examine the nature of activity-dependent biosynthesis of FMRP involved in another local translation-dependent process at synapses, mGluR- LTD. We find that mice with the Fragile X premutation exhibit impaired mGluR-dependent translation of dendritic FMRP and enhanced mGluR-LTD. The synaptic plasticity phenotype is shared with Fragile X Syndrome model mice, yet involves a distinct underlying mechanism, suggesting a possible mechanism for cognitive defects in premutation carriers.