Box 1. Long-term potentiation.

Long-term potentiation (LTP) refers to a persistent strengthening of a synaptic connection in response to a specific firing pattern of presynaptic neurons. It was discovered in the rabbit hippocampus in 1966 by the Norwegian physiologist Terje Lømo and since then it has been widely studied as a neural substrate of memory and learning. Typically, at an excitatory synapse, a single action potential of a presynaptic neuron will cause an excitatory postsynaptic potential (EPSP) in the consecutive neuron. Both the amplitude and the duration of EPSPs can be altered by previous experience. In LTP, a high-frequency (100 Hz) train of stimuli, called a ‘tetanus’, causes a shift towards longer EPSPs with greater amplitudes, which are observed up to several days/weeks following tetanus. Different forms of LTP exist, with associative (NMDAR-dependent) and non-associative (NMDA-independent) LTP being one of the most prominent distinctions. In associative LTP, the presynaptic activity has to precede the firing of a postsynaptic neuron (“Hebb’s rule”). This enables the simultaneous occurrence of two events at the NMDARs - namely, the opening of an NMDAR channel and the expulsion of the Mg2+ ion, which blocks the channel at resting membrane potential. This causes a major depolarization of the neuronal membrane, as well as an influx of Ca2+ through the NMDARs and subsequent activation of downstream signaling pathways (ex. Ca2+/calmodulin-dependent protein kinase II - CAMKII, protein kinase C - PKC), which causes the recruitment of AMPARs from internal stores during early LTP and de novo AMPAR synthesis in late LTP. In non-associative LTP, the Ca2+ influx into the presynaptic terminal, together with Ca2+ release from its internal pools caused by the tetanus, leads to an increased glutamate release probability during future action potentials. Non-associative LTP is therefore independent from postsynaptic activity.