Abstract
Timing and temporal precision of action potential generation are thought to be important for encoding of information in the brain. The ability of single neurons to transform their input into output action potential is primarily determined by intrinsic excitability. Particularly, plastic changes in intrinsic excitability represent the cellular substrate for spatial memory formation in CA1 pyramidal neurons (CA1-PNs). Here, we report that synaptically activated mGluR5-signaling can modulate the intrinsic excitability of CA1-PNs. Specifically, high-frequency stimulation at CA3-CA1 synapses increased firing rate and advanced spike onset with an improvement of temporal precision. These changes are mediated by mGluR5 activation that induces cADPR/RyR-dependent Ca2+ release in the dendrites of CA1-PNs, which in turn causes an increase in persistent Na+ currents (INa,P) in the dendrites. When group I mGluRs in CA1-PNs are globally activated pharmacologically, afterdepolarization (ADP) generation as well as increased firing rate are observed. These effects are abolished by inhibiting mGluR5/cADPR/RyR-dependent Ca2+ release. However, the increase in firing rate, but not the generation of ADP is affected by inhibiting INa,P. The differences between local and global activation of mGluR5-signaling in CA1-PNs indicates that mGluR5-dependent modulation of intrinsic excitability is highly compartmentalized and a variety of ion channels are recruited upon their differential subcellular localizations. As mGluR5 activation is induced by physiologically plausible brief high-frequency stimulation at CA3-CA1 synapses, our results suggest that mGluR5-induced enhancement of dendritic INa,P in CA1-PNs may provide important implications for our understanding about place field formation in the hippocampus.
Highlights
The hippocampus is a major part of the brain responsible for spatial learning and memory
We have recently demonstrate that highfrequency stimulation (HFS) of the Schaffer collateral pathway leads to the reliable activation of postsynaptic mGluR5 in CA1 pyramidal neurons (CA1-PNs), producing the short-term potentiation of EPSP-to-spike (E-S) coupling [32]
HFS-induced Metabotropic glutamate receptors (mGluRs) activation causes increases in action potential (AP) firing and its temporal precision We recently reported that high-frequency stimulations (HFS; 100 Hz for 0.5 s) to Schaffer Collateral (SC) synapses trigger mGluR-dependent Ca2+ release in apical dendrites of CA1-PN, which in turn induce calmodulin-dependent increase in persistent Na current (INa,P) that leads to E-S potentiation [32]
Summary
The hippocampus is a major part of the brain responsible for spatial learning and memory. When animals navigate large environments, a subset of hippocampal pyramidal neurons termed ‘place cells’ encode the spatial information. These cells exhibit location-specific increases in firing frequency when the animal traverses a specific location known as a place field [18]. Understanding of the underlying mechanisms that contribute to the activity-induced modulation of firing frequency is Plasticity in the hippocampus has been strongly implicated in spatial memory formation [22, 27]. CA1-PNs that later become place cells showed a lower AP threshold and an increased likelihood of firing [2] These results imply the importance of the modulation of
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