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• W2892231531 abstract "Plasticity in brain synapses and circuits is thought to underlie learning and the formation of new memories. The seminal work of Bliss and Lomo (1973) found that in the rabbit hippocampus, at the perforant path synapse with dentate granule cells, excitatory postsynaptic potentials (EPSPs) increased in amplitude after high frequency stimulation. This persistent synaptic enhancement was termed long-term potentiation (LTP). They also detected a change in the relationship between the EPSP and population spike amplitude suggesting neuronal excitability also has plastic properties. This second component of plasticity was termed EPSP-spike or E-S potentiation. A wealth of studies has examined LTP in different brain areas since then, and the Schaffer collateral–CA1 synapse of the hippocampus has become the classical example of LTP. This LTP is input specific, durable and depends on the activation of NMDA receptors (Sjöström et al. 2008). In contrast, EPSP-spike potentiation seems to depend in part on GABAergic modulation (Staff & Spruston, 2003). Furthermore, voltage-gated conductances of postsynaptic CA1 neurons can be modulated in an activity dependent manner leading to local or global changes in excitability (Frick et al. 2004; Fan et al. 2005). The article by Yu et al. in this issue of The Journal of Physiology describes medium term changes in intrinsic excitability in CA1 pyramidal cell dendrites induced by a classical LTP protocol (Yu et al. 2018). As did Bliss and Lomo, the authors used high frequency electrical stimulation (tetanic stimulation) to induce plastic changes. They also excluded, by pharmacological means, NMDA receptor dependent modifications to avoid long-term synaptic enhancement of the EPSP. By applying a GABAA receptor blocker, the study isolated metabotropic glutamate receptor (mGluR) dependent plasticity. In these pharmacologically stringent conditions, the work of Yu et al. revealed a post-tetanic potentiation of EPSP-spike coupling in CA1 pyramidal neurons. High frequency stimulation of Schaffer collaterals induced action potential firing in postsynaptic neurons, activated metabotropic glutamate receptor 5 (mGluR5) signalling, and transiently increased calcium in regions of apical dendrites. Tetanic stimuli, in these conditions, did not change the amplitudes of excitatory postsynaptic currents (EPSCs) or their paired-pulse ratio. However, EPSP amplitudes were significantly increased, pointing to changes in dendritic excitability including the upregulation of an amplifying persistent sodium current. The paper shows a post-tetanic increase in spike probability, abolished by low doses of tetrodotoxin, and a small but significant hyperpolarization of the firing threshold voltage. The mechanisms of this E-S potentiation were carefully dissected in experiments based on pharmacology, calcium imaging, transgenic mice and RNA interference. The underlying signalling cascade was shown to involve an increase in calcium, and a consequent calmodulin dependent upregulation of Nav1.6, which mediates a persistent sodium current, INaP. With a low activation voltage, INaP amplifies EPSPs at subthreshold voltages and so decreases the threshold for action potential initiation. Post-tetanic potentiation of EPSP-spike coupling differs from Schaffer collateral LTP. It is short lasting (about 2 min), independent of NMDA receptors, and dendritic excitability is enhanced. The probability of action potential generation in response to synaptic stimuli increases, not only for Schaffer collateral synapses, but also for distal perforant path synapses. These differences are linked, however, to an identical induction protocol for E-S potentiation and classical synaptic LTP. What could be the physiological role of mGluR5 dependent E-S potentiation in parallel with synaptic NMDA receptor dependent changes? Interactions between synaptic and intrinsic changes may be complex. Yu and colleagues suggest that post-tetanic modulation of dendritic excitability could provide an instructive signal for potentiation of distal inputs, in particular perforant path inputs from the entorhinal cortex. It is tempting to speculate. Could post-tetanic E-S potentiation promote the formation of new place fields in CA1? Previous studies have shown that cellular properties strongly influence neuronal responses to inputs during behaviour. An increased intrinsic excitability could convert a silent CA1 cell receiving spatially tuned input into a functional firing place cell (Lee et al. 2012). Possibly mGluR5 mediated E-S potentiation acts as a gate-keeper, facilitating associations between contextual information from CA3 and location information from entorhinal cortex (Bittner et al. 2015) but without requiring highly correlated interaction between these two inputs. It is notoriously difficult to show how synaptic and cellular forms of plasticity contribute to learning and spatial memory function relevant to an animal. Future studies are required to appreciate how synaptic plasticity and cellular corollaries could work together over behavioural time scales (Bittner et al. 2017). This convincing molecular dissection of signalling cascades for post-tetanic E-S potentiation sets the stage for in vivo studies linking plasticity of neuronal INaP to the formation of memories. None declared." @default.
• W2892231531 created "2018-09-27" @default.
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• W2892231531 date "2018-07-05" @default.
• W2892231531 modified "2023-09-25" @default.
• W2892231531 title "Beyond LTP: increasing the safety factor for spike initiation" @default.
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• W2892231531 doi "https://doi.org/10.1113/jp276604" @default.
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