When depolarized, Hippocampal pyramidal cells (HPCs), typically fire an initial burst of a few action potentials at high frequency (circa 80-200 Hz) before accommodating to either fire at lower frequency or and stop firing altogether. Similar high frequency burst firing can be observed in vivo, for example in the in the activity of place cells, and is thought to be important for the generation of long-lasting synaptic plasticity (for example LTP) at the excitatory synapses HPCs form with various downstream neurones. Changes to such high frequency bursting can also be seen associated with models of human disease including epilepsy and Alzheimer’s disease. The ionic conductances that underpin the high frequency bursting of HPCs are also those which produce the fast afterdepolarizing potential which follows the firing of a single action potential in these cells. Although the complement of ion channels that produce this ADP is not entirely understood, pharmacological studies have revealed that agents which enhance this ADP, for example Kv7 channel antagonists, promote burst firing (and can be pro-cognitive/pro-convulsant), whereas compounds which depress the ADP, for example retigabine, inhibit bursting and are anticonvulsant. Our recent studies of hippocampal slice in vitro have revealed that the ADP amplitude in HPCs, and consequently the propensity of these cells to exhibit high frequency bursting, is subject to multiple activity-dependent forms of persistent intrinsic plasticity. In our first investigations (Brown and Randall, 2009) we demonstrated that various defined, brief patterns of activity elicited in the cell under investigation produced a long-lasting (>30 min) depression of the ADP, and an accompanying reduction in high frequency firing ability. This appeared to be due to the up-regulation of Kv7 channel activity. In a subsequent study (Brown, Booth and Randall 2011) we first demonstrated that in CA3 pyramidal cells a period of pharmacological activation of mGluR1 produced a long-lasting depression of the ADP and a parallel reduction in burstyness. We then demonstrated that this action could be mimicked by synaptically-mediated activation of mGluR1 produced by suitable electrical stimulation of the associational commissural pathway. Unlike the depression produced by cell-intrinsic conditioning stimuli, the persistent depression of the ADP produced by mGluR1 activation was not mediated by changes to Kv7 channels, since it still occurred in the presence of the Kv7 blocker XE-991. Furthermore, mGluR1-mediated depression of the ADP was not blocked by intracellular BAPTA, suggesting changes in intracellular Ca2+ levels are not involved in this process. In combination, our work reveals that in HPCs the fast ADP, and thus ability to produce fast spike bursts, is under dynamic regulation through multiple pathways. This may have implications for both normal CNS function, for example the ability to produce LTP, and pathological states such as epilepsy, as discussed recently by others (Schorge and Walker 2009).