Complex-learning Induced Modifications in Synaptic Inhibition: Mechanisms and Functional Significance

Following training in a difficult olfactory-discrimination (OD) task rats acquire the capability to perform the task easily, with little effort. This new acquired skill, of ‘learning how to learn’ is termed ‘rule learning’. At the single-cell level, rule learning is manifested in long-term enhancement of intrinsic neuronal excitability of piriform cortex (PC) pyramidal neurons, and in excitatory synaptic connections between these neurons to maintain cortical stability, such long-lasting increase in excitability must be accompanied by paralleled increase in inhibitory processes that would prevent hyper-excitable activation. In this review we describe the cellular and molecular mechanisms underlying complex-learning-induced long-lasting modifications in GABA _A -receptors and GABA _B -receptor-mediated synaptic inhibition. Subsequently we discuss how such modifications support the induction and preservation of long-term memories in the in the mammalian brain. Based on experimental results, computational analysis and modeling, we propose that rule learning is maintained by doubling the strength of synaptic inputs, excitatory as well as inhibitory, in a sub-group of neurons. This enhanced synaptic transmission, which occurs in all (or almost all) synaptic inputs onto these neurons, activates specific stored memories. At the molecular level, such rule-learning-relevant synaptic strengthening is mediated by doubling the conductance of synaptic channels, but not their numbers. This post synaptic process is controlled by a whole-cell mechanism via particular second messenger systems. This whole-cell mechanism enables memory amplification when required and memory extinction when not relevant.