Membrane Lipids Tune Synaptic Transmission by Direct Modulation of Presynaptic Potassium Channels

Abstract

Voltage-gated potassium (Kv) channels are involved in action potential (AP) repolarization in excitable cells. Exogenous application of membrane-derived lipids, such as arachidonic acid (AA), regulates the gating of Kv channels. Whether membrane-derived lipids released under physiological conditions have an impact on neuronal coding through this mechanism is unknown. We show that AA released in an activity-dependent manner from postsynaptic hippocampal CA3 pyramidal cells acts as retrograde messenger, inducing a robust facilitation of mossy fiber (Mf) synaptic transmission over several minutes. AA acts by broadening presynaptic APs through the direct modulation of Kv channels. This form of short-term plasticity can be triggered when postsynaptic cell fires with physiologically relevant patterns and sets the threshold for the induction of the presynaptic form of long-term potentiation (LTP) at hippocampal Mf synapses. Hence, direct modulation of presynaptic Kv channels by activity-dependent release of lipids serves as a physiological mechanism for tuning synaptic transmission.

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“…Therefore, the modulation of the composition of its fatty acyl chains can potentially affect neuronal functioning, at least in part through altered function of membrane-bound proteins. 19, 20 In our study we performed another level of analysis focusing on the fatty acyl chain profile. Our data shows that CUS led to a significant alteration in the fatty acyl chain profile of phospholipids and DG, with increased levels of long chain fatty acyls with 38 carbons (38C) and an increase in polyunsaturated fatty acyls with 4 double bonds in the hippocampus (Figure 3).…”

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“…2a). In addition, arachidonic acid (AA), which is both a precursor (in a lipid-esterified form) and a degradation product of eCBs, has recently been found to also act as a retrograde messenger, potentiating excitatory transmission in a process called depolarization-induced potentiation of excitation (DPE) 31 (FIG. 2b).…”

“…b | Schematic presentation of the modulation of excitatory transmission by the eCB precursor and degradation product arachidonic acid (AA). Postsynaptic AA acts in a retrograde manner via inhibition of presynaptic voltage-gated potassium (Kv) channels and potentiation of excitatory neurotransmission, a process called depolarization-induced potentiation of excitation (DPE) 31 . PKA, protein kinase A.…”

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“…Based on a combination of their distinct functional properties and subcellular localizations, the Kv1 and Kv3 channels at the calyx of Held, like those in MFs and BCTs, have distinct roles, with preterminal Kv1.1/Kv1.2 channels reducing nerve terminal excitability and preventing aberrant neurotransmitter release, and Kv3 channels within the terminal shortening the presynaptic action potential to regulate neurotransmitter release (Ishikawa et al, 2003). A recent study suggests Kv1 and Kv3 channels near/at MF terminals are substrates for a novel form of plasticity, whereby arachidonic acid released as a retrograde messenger from CA3 dendrites/spines inhibits these KChs, resulting in a broadening of action potentials and an increase in glutamate release (Carta et al, 2014). In heterologous cells, arachidonic acid enhances inactivation to suppress activity of Kv1 and Kv3 channels, while PIP2 removes inactivation and enhances their activity (Oliver et al, 2004).…”