Plasticity of Intrinsic Excitability during Long-Term Depression Is Mediated through mGluR-Dependent Changes inI_hin Hippocampal CA1 Pyramidal Neurons

Abstract

Bidirectional changes in synaptic strength are the proposed cellular correlate for information storage in the brain. Plasticity of intrinsic excitability, however, may also be critical for regulating the firing of neurons during mnemonic tasks. We demonstrated previously that the induction long-term potentiation was accompanied by a persistent decrease in CA1 pyramidal neuron excitability (Fan et al., 2005). We show here that induction of long-term depression (LTD) by 3 Hz pairing of back-propagating action potentials with Schaffer collateral EPSPs was accompanied by an overall increase in CA1 neuronal excitability. This increase was observed as an increase in the number of action potentials elicited by somatic current injection and was caused by an increase in neuronal input resistance. After LTD, voltage sag during hyperpolarizing current injections and subthreshold resonance frequency were decreased. All changes were blocked by ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride), suggesting that a physiological loss of dendritic h-channels was responsible for the increase in excitability. Furthermore, block of group 1 metabotropic glutamate receptors (mGluRs) or protein kinase C prevented the increase in excitability, whereas the group 1 mGluR agonist DHPG [(RS)-3,5-dihydroxyphenylglycine] mimicked the effects. We conclude that 3 Hz synaptic stimulation downregulates I h via activation of group 1 mGluRs and subsequent stimulation of protein kinase C. We propose these changes as part of a homeostatic and bidirectional control mechanism for intrinsic excitability during learning.

Mechanisms of heterosynaptic metaplasticity

“…Indeed, during visual cortex development, BCM-like metaplasticity is governed by activity-dependent regulation of the NMDA receptor subunit composition [14,15], an expression mechanism that also underlies certain metaplasticity effects in the hippocampus [16]. However, others have proposed that heterosynaptic metaplasticity can be mediated by a widespread modification of cellular excitability through changes in ion channels that control the discharge properties of neurons such as I h or the slow afterhyperpolarization, for which there is experimental support [17][18][19][20][21]. It should be noted that these various potential expression mechanisms are not mutually exclusive.…”

Computation by oscillations: Implications of experimental data for theoretical models of grid cells

“…Changes in traditional Hebbian LTP and long-term depression during development could result in an increase or decrease in the spatial wavelength. The h-current, which shows changes in its kinetics along the dorsal-ventral axis, has been shown to interact with both LTP and longterm depression in the hippocampus (Nolan et al, 2004;Fan et al, 2005;Brager and Johnston, 2007). In the hippocampus, LTP causes an increase in I(h) and a subsequent decrease in excitability, while long-term depression causes a decrease in I(h) and a subsequent increase in excitability (Fan et al, 2005;Brager and Johnston, 2007).…”

“…The h-current, which shows changes in its kinetics along the dorsal-ventral axis, has been shown to interact with both LTP and longterm depression in the hippocampus (Nolan et al, 2004;Fan et al, 2005;Brager and Johnston, 2007). In the hippocampus, LTP causes an increase in I(h) and a subsequent decrease in excitability, while long-term depression causes a decrease in I(h) and a subsequent increase in excitability (Fan et al, 2005;Brager and Johnston, 2007). Knockout of the HCN1 subunit causes enhanced LTP in the hippocampus (Nolan et al, 2004), potentially by suppressing calcium spikes in the distal dendrites of pyramidal cells (Tsay et al, 2007).…”

HCN channels enhance spike phase coherence and regulate the phase of spikes and LFPs in the theta-frequency range

“…From a single-neuron perspective, HCN channels in CA1 pyramidal neurons play a critical role in regulating neuronal integration and excitability (14,(24)(25)(26)(27) and importantly introduce an inductive phase lead in the voltage response to theta-frequency oscillatory inputs (28), thereby enabling intraneuronal synchrony of incoming theta-frequency inputs (29). Given these and their predominant dendritic expression (25), we hypothesized HCN channels as regulators of LFPs through their ability to alter the amplitude and phase of the intracellular voltage response, thereby altering several somatodendritic transmembrane currents that contribute to LFPs.…”