Regulation of synaptic signalling by postsynaptic, non-glutamate receptor ion channels

Abstract

Activation of glutamatergic synapses onto pyramidal neurons produces a synaptic depolarization as well as a buildup of intracellular calcium (Ca(2+)). The synaptic depolarization propagates through the dendritic arbor and can be detected at the soma with a recording electrode. Current influx through AMPA-type glutamate receptors (AMPARs) provides the depolarizing drive, and the amplitudes of synaptic potentials are generally thought to reflect the number and properties of these receptors at each synapse. In contrast, synaptically evoked Ca(2+) transients are limited to the spine containing the active synapse and result primarily from Ca(2+) influx through NMDA-type glutamate receptors (NMDARs). Here we review recent studies that reveal that both synaptic depolarizations and spine head Ca(2+) transients are strongly regulated by the activity of postsynaptic, non-glutamate receptor ion channels. In hippocampal pyramidal neurons, voltage- and Ca(2+)-gated ion channels located in dendritic spines open as downstream consequences of glutamate receptor activation and act within a complex signalling loop that feeds back to regulate synaptic signals. Dynamic regulation of these ion channels offers a powerful mechanism of synaptic plasticity that is independent of direct modulation of glutamate receptors.

Figure 1. Multiple and distinct sets of VSCC classes contribute to bAP-mediate Ca²⁺ transients in spines and dendrites

A, image of a spiny apical dendrite filled with 5 μm Alexa Fluor-594 (red fluorescence) and the Ca²⁺ indicator 150 μm Fluo-5F (green fluorescence). B, fluorescence collected in a line scan across the spine (sp) and dendrite (den) shown in panel A during stimulation of a bAP by somatic current injection. A bAP (white trace, top) rapidly increases green fluorescence in the spine and dendrite, indicating increased [Ca²⁺] in both compartments. C, quantification of the fluorescence transients (ΔG_bAP/G_sat) in the spine head (middle) and neighbouring dendrite (bottom) evoked by a bAP (top). The continuous lines and shaded regions depict the averages ± the standard errors of the mean (s.e.m.), respectively. D, summary of the contribution of each VSCC class to the bAP-evoked Ca²⁺ transients measured in spines in response to a single bAP. The ΔG_bAP/G_sat measured in the absence (‘none’) and in the presence (‘all’) of all the VSCC antagonists is also plotted. E, as in panel D for bAP-evoked Ca²⁺ transients measured in the dendrite. # and * indicate statistically significant (P < 0.05) differences compared to control conditions (‘none’) or the condition including all VSCC blockers (‘all’), respectively.

Figure 2. Differential regulation of uEPSP and Δ[Ca²⁺]_syn by multiple, non-glutamate receptor ion channels

A, 2PLSM image of a spiny region of apical dendrite of a CA1 hippocampal pyramidal neuron filled with 10 μm Alexa Fluor-594 (red fluorescence) and 300 μm of Fluo-5F (green fluorescence). B, fluorescence collected in a line that intersects the spine head (sp) and neighbouring dendrite (den) shown in panel A during glutamate uncaging onto the spine head. The arrowheads in A and B indicate the location and timing, respectively, of a 500 μs pulse of 725 nm laser light used to trigger 2-photon mediated photolysis of MNI-glutamate. The increase in green fluorescence indicates increased intracellular [Ca²⁺]. The white trace shows the uEPSP recorded simultaneously at the soma. C, uEPSP (top) and ΔG_syn/G_sat (bottom) measured in control conditions. The continuous lines and shaded regions depict the averages ± the standard errors of the mean (s.e.m.), respectively. D and E, summary of the amplitudes of the uEPSP (D) and ΔG_syn/G_sat (E) in a variety of pharmacological conditions. The effect of each antagonist was measured in absence (black bars) or in the presence of the SK antagonist apamin (red bars). *P < 0.05 for each apamin condition compared to the corresponding apamin-free condition. #P < 0.05 compared to control condition – i.e. in the absence of all antagonists.

Figure 3. A model of the regulation of spine head Ca²⁺ transients by ionotropic glutamate receptors, voltage-gated Na⁺ and Ca²⁺ channels, and SK channels

Glutamate release activates AMPARs and NMDARs in the spine. AMPAR opening increases the potential in the spine (V_spine), enhancing current flow through NMDARs by relief of Mg²⁺ block. The local depolarization also activates a variety of VSCCs and voltage-sensitive Na⁺ channels (VSSCs) that contribute additional depolarization or Ca²⁺ entry into the spine. Ca²⁺ through Ca_V2.3 channels specifically activates SK channels that repolarize the spine and terminate NMDAR signalling. Channels whose modulation could serve as glutamate-receptor independent mechanisms of synaptic plasticity are shown in grey (Bloodgood & Sabatini, 2007b).