Astroglial potassium clearance contributes to short‐term plasticity of synaptically evoked currents at the tripartite synapse

Abstract

Key points• Astrocytes, active players in neurotransmission, display complex membrane ionic responses upon neuronal activity.• However, the nature, plasticity and role of the activity-dependent astroglial currents on synaptic plasticity remain unclear in the hippocampus.• We here demonstrate, using simultaneous electrophysiological recordings of hippocampal neurons and astrocytes, that the complex astroglial current induced synaptically is dominated (80%) by potassium entry through K ir 4.1 channels and also includes, in addition to the glutamate transporter current, a small residual current, partially mediated by GABA transporters and K ir 4.1-independent potassium channels.• These synaptically evoked astroglial currents exhibit differential short-term plasticity patterns, and astroglial potassium uptake mediated by K ir 4.1 channels down-regulates hippocampal short-term plasticity.• This study establishes astrocytes as integrators of excitatory and inhibitory synaptic activity, which may, through dynamic potassium handling, define the signal-to-noise ratio essential for specific strengthening of synaptic contacts and synchronization of neuronal ensembles, a prerequisite for learning and memory.Abstract Astroglial processes enclose ∼60% of CA1 hippocampal synapses to form the tripartite synapse. Although astrocytes express ionic channels, neurotransmitter receptors and transporters to detect neuronal activity, the nature, plasticity and impact of the currents induced by neuronal activity on short-term synaptic plasticity remain elusive in hippocampal astrocytes. Using simultaneous electrophysiological recordings of astrocytes and neurons, we found that single stimulation of Schaffer collaterals in hippocampal slices evokes in stratum radiatum astrocytes a complex prolonged inward current synchronized to synaptic and spiking activity in CA1 pyramidal cells. The astroglial current is composed of three components sensitive to neuronal activity, i.e. a long-lasting potassium current mediated by K ir 4.1 channels, a transient glutamate transporter current and a slow residual current, partially mediated by GABA transporters and K ir 4.1-independent potassium channels. We show that all astroglial membrane currents exhibit activity-dependent short-term plasticity. However, only the astroglial glutamate transporter current displays neuronal-like dynamics and plasticity. As K ir 4.1 channel-mediated potassium uptake contributes to 80% of the synaptically evoked astroglial current, we investigated in turn its impact on short-term synaptic plasticity. Using glial conditional K ir 4.1 knockout mice, we found that astroglial potassium uptake reduces synaptic responses to repetitive stimulation and post-tetanic potentiation. These results show that astrocytes integrate synaptic activity via multiple ionic channels and transporters and contribute to short-term plasticity in part via potassium clearance mediated by K ir 4.1 channels.

Neuron-glia cross talk revealed in reverberating networks by simultaneous extracellular recording of spikes and astrocytes' glutamate transporter and K+ currents

“…Such sP signals 1 ) were time-locked to network bursts, 2 ) had peak amplitudes often larger than 1–2 mV, in mature networks, with an ∼250-ms delay relative to the burst start, 3 ) were abolished by TTX (0.2 μM), and 4 ) had larger amplitudes when network activity was increased by blocking the GABA A receptors with gabazine (GZ; 3 μM). The sP time course resembled the reported kinetics of [K + ] o changes (Amzica and Neckelmann 1999; Frankenhaeuser and Hodgkin 1956; Orkand et al 1966) and were consistent with Kir current kinetics (Butt and Kalsi 2006; De Saint Jan and Westbrook 2005; Maldonado et al 2013; Sibille et al 2014). To test the extent to which sPs depended on Kir channels, we applied 30 μM Ba 2+ , which potently blocks Kir (Butt and Kalsi 2006) but is poorly effective on two-pore K + channels (Zhou et al 2009).…”

“…GluT currents precede the long-lasting Ba 2+ -sensitive K + current and are selectively blocked by TBOA (Bergles and Jahr 1997; Diamond et al 1998; Lüscher et al 1998; Sibille et al 2014). Because GluT (particularly GLT-1) expression strongly increases in the first 10 days of primary hippocampal cultures (Perego et al 2000), we applied TBOA from 11 to 13 DIV ( n = 3; Fig.…”

Translation in astrocyte distal processes sets molecular heterogeneity at the gliovascular interface

“…Astrocyte endfeet are interfacing vessels and neurons, and control mechanisms such as BBB integrity, basal lamina composition, immune quiescence and vessel contractility, as well as neuronal activity by funneling among others extracellular potassium and glutamate [4, 7]. These functions might well be controlled by local RNA synthesis at the endfeet, as suggested by the local translation of Aqp4, Kir4.1 and Glt-1, which are key regulators of the perivascular and neuronal homeostasis [56, 57]. Local translation in astrocyte endfeet might also be involved in neurological disorders as demonstrated in neurons in the case of X-fragile syndrome [58], amyotrophic lateral sclerosis [59, 60] or spinal muscular atrophy [61, 62].…”

Cell Biology of Astrocyte-Synapse Interactions

“…Astrocytes then break down excess glutamate into glutamine and shuttle it back to neurons to provide the building blocks for ongoing synaptic transmission (Tani et al, 2014). Similarly, through numerous channels, astrocytes control the ionic balance at the synapse including potassium ions, which is crucial for sustainability of proper synaptic transmission (Djukic et al, 2007; Kuffler, 1967; Sibille et al, 2014). …”