Associating synaptic and intrinsic plasticity

Activity-dependent changes modulating the impact of a presynaptic discharge on the postsynaptic firing probability form the basis for memory storage in the brain. This impact is determined by two factors, the synaptic efficacy itself and the intrinsic excitability of the neuron, both of which can undergo activity-dependent plasticity. The link between long-term potentiation/depression (LTP/LTD) and the potentiation/depression of intrinsic plasticity has, however, been left largely unexplored. In this issue of The Journal of Physiology, Campanac and Debanne (Campanac & Debanne, 2008), using CA1 pyramidal neurons of rat hippocampal slices, show that there is indeed an intimate link between LTP/LTD and at least one form of potentiation/depression of intrinsic excitability. These two forms of plasticity act synergistically to boost the impact of a presynaptic neuron on the firing probability of the postsynaptic neuron. Already in the first description of LTP it was noted that besides the enhancement of the EPSP magnitude itself there was also, at a given EPSP magnitude, a larger population spike (Bliss & Lomo, 1973). This latter phenomenon was later termed EPSP-to-spike (E-S) potentiation (Andersen et al. 1980) and two main mechanisms were put forward to explain it, a synaptic (Abraham et al. 1987) and an intrinsic (Hess & Gustafsson, 1990) mechanism. The synaptic explanation is based on the fact that the synaptically evoked firing of the postsynaptic neuron depends on the balance between excitation and feed-forward inhibition, and that this balance is shifted as a result of LTP induction. However, there is now reason to believe that synaptic transmission onto interneurons also undergoes LTP, keeping the balance between synaptic excitation and inhibition onto principal neurons intact (Lamsa et al. 2005). If so, this experimentally observed synaptic component of E-S potentiation may largely be an experimental artifact. This is because in the experimental situation, unlike in real life, a variable portion of the feed-forward inhibition is evoked by direct stimulation of the inhibitory interneuron axons (thereby by-passing the synaptic excitation of the interneuron). The second explanation for the E-S potentiation, an increased intrinsic excitability of the postsynaptic neuron, has received considerable support in recent years (Zhang & Linden, 2003; Frick & Johnston, 2005). The main question asked in the paper by Campanac and Debanne is whether the induction of E-S potentiation/depression requires the same timing for pre- and postsynaptic activity as the induction of LTP/LTD does. The authors induce plasticity by repeatedly (100–150 times) pairing a single EPSP with a single postsynaptic spike under pharmacological blockade of synaptic inhibition (to isolate the intrinsic excitability factor). In line with previous studies on spike timing-dependent plasticity LTP is induced when the EPSP precedes the spike (< 50 ms), and LTD is induced when the EPSP follows the spike (< 50 ms). What Campanac and Debanne found was that the induction of E-S potentiation/depression exhibits the same timing requirements as LTP/LTD. Moreover, NMDA receptor blockade inhibited not only LTP/LTD, but also the E-S potentiation/depression. The synaptic and intrinsic plasticities are thus linked to the same type of NMDA receptor-dependent induction. However, to what extent these two forms of plasticity continue to be linked also after the induction remains to be explored. For example, how parallel are the time courses of the simultaneously induced synaptic and intrinsic plasticity? Campanac and Debanne go on to show that LTP/LTD was associated with larger/smaller EPSP amplitudes for a given rising slope of the EPSP. These changes of the EPSP amplitude–slope relationship are likely to be responsible for the changes in E-S coupling observed in these experiments and it is conceivable that these changes are caused by modulation of local dendritic voltage-gated channels, such as those underlying IA, Ih and INa. The authors describe that pharmacological blockade of such voltage-gated channels also mimics the observed changes of the EPSP amplitude–slope relationship. However, occlusion studies linking modulation of any of these channels to changes in E-S coupling remain to be done. Since calcium influx through synaptic NMDA receptors thus is the likely trigger also for the observed change in intrinsic plasticity, a functionally important point is how far away from the NMDA receptors this change can spread, i.e. how synapse-specific this plasticity is? Campanac and Debanne show that there is at least a certain degree of specificity since the changes in the E-S coupling and in the EPSP amplitude–slope relationship induced in synapses onto the middle portion of the apical dendrites did not spread to synapses onto the proximal dendrite. This result agrees with a previous study in the CA1 region showing that E-S potentiation (during blockade of synaptic inhibition) was input specific (at least not affecting synapses within the same dendritic region) (Hess & Gustafsson, 1990). This latter study showed, however, that stronger LTP induction induced heterosynaptic E-S potentiation (as well as large changes in the EPSP amplitude–slope relationship). In fact, there may exist a full range of spatial distributions of intrinsic plasticity depending on the nature of the triggering activity (Zhang & Linden, 2003), from changes affecting only the individual synapse, to involving smaller or larger portions of dendritic segments, to changes affecting all synapses (such as if the threshold for the action potential in the initial segment is modified (Xu et al. 2005)). These different forms of intrinsic plasticity most certainly have different roles, involving both mnemonic and non-mnemonic functions (Kim & Linden, 2007). In this perspective, the local form of intrinsic plasticity with associative induction requirements now described by Campanac and Debanne would appear to function as an associate to LTP/LTD in memory function.