Ultrastructural evidence for pre‐ and postsynaptic localization of Ca<sub>v</sub>1.2 L‐type Ca<sup>2+</sup> channels in the rat hippocampus

Tippens, Alyssa L.; Paré, Jean‐François; Langwieser, Nicolas; Moosmang, Sven; Milner, Teresa A.; Smith, Yoland; Lee, Amy

doi:10.1002/cne.21567

Cited by 103 publications

(75 citation statements)

References 76 publications

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“…Whereas the expression of NMDARs and L-VGCCs in astrocytes has been debated, our study is in line with previous studies reporting of the presence of these channels in astrocytes (43)(44)(45)(46)(47)(48)50). With respect to astrocyte NMDARs, we find that applying NMDA in the presence of TTX to prevent synaptic transmission directly triggers astrocyte membrane depolarization, and this depolarization is compromised by intracellularly infusing MK-801 or deleting GRIN1 in astrocytes.…”

Section: Discussionsupporting

confidence: 92%

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Letellier

Park

Chater

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

117

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Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-D-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca 2+ signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca 2+ channels. Intracellular infusion of NMDARs or Ca 2+-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocytedependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites.synapse heterogeneity | synaptic strength | astrocyte | hippocampal neuron | heterosynaptic plasticity A n enduring challenge in neurobiology is to understand how neurons set the strengths of their numerous synapses to efficiently process and store different information while maintaining network homeostasis. Electrophysiology and imaging approaches have revealed that synapses display a high degree of functional heterogeneity, even for those sharing the same axon or dendrite (1-3). The observation that synaptic strengths are heterogeneous, in turn, suggests that synapses can operate independently from one another. Accordingly, many studies have demonstrated the input-specificity of Hebbian and also of homeostatic forms of synaptic plasticity, where synaptic changes are restricted to inputs whose activity is altered (4-6). Nevertheless, such a synapse-autonomous behavior could potentially compromise the global network homeostasis by biasing the overall activity toward excitation or depression, and to overcome this issue, it has been proposed that distinct inputs cooperate by coordinating their relative strengths through heterosynaptic interactions (7-9). In support of the idea that synapses behave as interdependent rather than isolated functional units, the restriction of synaptic strength changes to active inputs has been demonstrated to break down at times, with the induction of synaptic plasticity in the stimulated input accompanying either synaptic depression or potentiation of the nonstimulated inputs (10-13). In a highly studied plasticity paradigm of long-term potentiation (LTP) at hippocampal Schaffer collateral-CA1 synapses, tetanic stimulation that induces LTP is often accompanied by presynaptic long-term depression (LTD) of nonstimulated Schaffer collat...

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Section: Discussionsupporting

confidence: 92%

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Letellier

Park

Chater

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

117

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“…Cav1.2 is widely expressed in the heart, pancreas, adrenal gland, and nervous system (Snutch et al, 1991;Dirksen and Beam, 1996). It has been shown that Cav1.2 is located both pre-and postsynaptically in the brain (Tippens et al, 2008) and is present on peripheral nerve axons (Enes et al, 2010). Data from 4-AP-treated samples were first normalized by using the loading (GAPDH) control and then normalized to the control group (without 4-AP).…”

Section: Discussionmentioning

confidence: 99%

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Chen

et al. 2014

Mol Pharmacol

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4-Aminopyridine (4-AP, fampridine) is used clinically to improve neuromuscular function in patients with multiple sclerosis, spinal cord injury, and myasthenia gravis. 4-AP can increase neuromuscular and synaptic transmission by directly stimulating high voltageactivated (HVA) Ca 21 channels independent of its blocking effect on voltage-activated K 1 channels. Here we provide new evidence that the potentiating effect of 4-AP on HVA Ca 21 channels depends on the specific combination of voltage-activated calcium channel a1 (Cava 1 ) and voltage-activated calcium channel b (Cavb) subunits. Among the four Cavb subunits examined, Cavb3 was the most significant subunit involved in the 4-AP-induced potentiation of both L-type and N-type currents. Of particular note, 4-AP at micromolar concentrations selectively potentiated L-type currents reconstituted with Cav1.2, a 2 d1, and Cavb3. In contrast, 4-AP potentiated N-type currents only at much higher concentrations and had little effect on P/Q-type currents. In a phrenic nerve-diaphragm preparation, blocking L-type Ca 21 channels eliminated the potentiating effect of low concentrations of 4-AP on end-plate potentials. Furthermore, 4-AP enhanced the physical interaction of Cav1.2 and Cav2.2 subunits to Cavb3 and also increased their trafficking to the plasma membrane. Site-directed mutagenesis identified specific regions in the guanylate kinase, HOOK, and C-terminus domains of the Cavb3 subunit crucial to the ability of 4-AP to potentiate L-type and N-type currents. Our findings indicate that 4-AP potentiates HVA Ca 21 channels by enhancing reciprocal Cav1.2-Cavb3 and Cav2.2-Cavb3 interactions. The therapeutic effect of 4-AP on neuromuscular function is probably mediated by its actions on Cavb3-containing L-type Ca 21 channels.

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“…Although their function is not entirely clear, they may control signal transmission in the axonal arborization. In addition, Cav1.2 (L-type) calcium channels that are sparsely expressed all over hippocampal soma and dendrites are prominently labeled by immunogold electron microscopy in hippocampal axons and in mossy fiber terminals (531).…”

Section: Channels In the Axon Terminalsmentioning

confidence: 99%

Axon Physiology

Debanne

Campanac

Bialowas

et al. 2011

Physiological Reviews

557

492

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Axons are generally considered as reliable transmission cables in which stable propagation occurs once an action potential is generated. Axon dysfunction occupies a central position in many inherited and acquired neurological disorders that affect both peripheral and central neurons. Recent findings suggest that the functional and computational repertoire of the axon is much richer than traditionally thought. Beyond classical axonal propagation, intrinsic voltage-gated ionic currents together with the geometrical properties of the axon determine several complex operations that not only control signal processing in brain circuits but also neuronal timing and synaptic efficacy. Recent evidence for the implication of these forms of axonal computation in the short-term dynamics of neuronal communication is discussed. Finally, we review how neuronal activity regulates both axon morphology and axonal function on a long-term time scale during development and adulthood.

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Ultrastructural evidence for pre‐ and postsynaptic localization of Ca_v1.2 L‐type Ca²⁺ channels in the rat hippocampus

Cited by 103 publications

References 76 publications

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Axon Physiology

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Ultrastructural evidence for pre‐ and postsynaptic localization of Cav1.2 L‐type Ca2+ channels in the rat hippocampus

Cited by 103 publications

References 76 publications

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Axon Physiology

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Ultrastructural evidence for pre‐ and postsynaptic localization of Ca_v1.2 L‐type Ca²⁺ channels in the rat hippocampus