Theoretical and modeling studies demonstrate that heterosynaptic plasticity – changes at synapses inactive during induction – facilitates fine-grained discriminative learning in Hebbian-type systems, and helps to achieve a robust ability for repetitive learning. A dearth of tools for selective manipulation has hindered experimental analysis of the proposed role of heterosynaptic plasticity in behavior. Here we circumvent this obstacle by testing specific predictions about changes in heterosynaptic plasticity, and associated behavioral consequences, following experimental manipulation of adenosine A1 receptors (A1R). We show that, compared to wild-type controls, A1R-knockout mice have impaired synaptic plasticity in visual cortex neurons, coupled with significant deficits in visual discrimination learning. Deficits in A1R-knockouts were seen specifically during re-learning, becoming progressively more apparent with learning on sequential visual discrimination tasks of increasing complexity. These behavioral results confirm our model predictions, and provide the first experimental evidence for a proposed role of heterosynaptic plasticity in learning.
bioRxiv Subject Collection: Neuroscience