Mechanisms for L-channel-mediated increase in [Ca2+] and its reduction by anti-bipolar drugs in cultured astrocytes combined with its mRNA expression in freshly isolated cells support the importance of astrocytic L-channels

Yan, Enzhi; Gu, Leyi; Hertz, Leif; Peng, Liang

doi:10.1016/j.ceca.2013.08.002

Cited by 36 publications

(36 citation statements)

References 70 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: 81%

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: 81%

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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“…In the present work, we have observed the decrease of TRPC1 expression in cultured cerebellar granule cells, cultured cerebral cortical neurones and freshly isolated neurones from the brains in vivo . Previously, we reported similar drug effect in astrocytes (Yan et al, 2013). Secondly, we found a substantial decrease in the SOCE in cerebellar granule cells exposed to each of the three drugs.…”

Section: Discussionsupporting

confidence: 70%

“…We have found several genes that are regulated by chronic treatment with anti-bipolar drugs in astrocytes (for review, see Peng et al, 2016). These includes down-regulation of gene expression of glutamate kainate receptor GluK2 (Li et al, 2009), the Ca 2+ -dependent phospholipase A 2 (Li et al, 2007) and transient receptor potential channel 1 (TRPC1); a cation channel, which in astroglia is activated by ER store depletion and contributes to the store-operated Ca 2+ entry, SOCE (Yan et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Chronic Treatment with Anti-bipolar Drugs Down-Regulates Gene Expression of TRPC1 in Neurones

Rong

Feng

et al. 2017

Front. Cell. Neurosci.

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In the brain, TRPC1 channels are abundantly expressed in neurones virtually in all regions; these proteins function as receptor-activated ion channels and are implicated in numerous processes, being specifically important for neurogenesis. Primary cultures of mouse cerebellar granule cell, cerebral cortical neurones, and freshly isolated neurones from in vivo brains were used to study effects of chronic treatment with anti-bipolar drugs [carbamazepine (CBZ), lithium salts and valproic acid] on gene expression of TRPC1. Expression of TRPC1 mRNA was identified with reverse transcription-polymerase chain reaction, whereas protein content was determined by Western blotting. Store-operated plasmalemmal Ca2+ entry (SOCE) was measured with fura-2 based microfluorimetry. Chronic treatment with each of the three drugs down-regulated mRNA and protein expression in cultured cerebellar granule cells in a time- and concentration-dependent manner. Similar effect was also observed in cultured cerebral cortical neurones treated with CBZ, lithium salts and valproic acid and in freshly isolated neurones from the brains of CBZ-treated animals. The amplitude of SOCE was substantially decreased in cerebellar granule cells chronically treated with each of the three drugs. Our findings indicate that down-regulation of TRPC1 gene expression and function in neurones may be one of the mechanisms of anti-bipolar drugs action.

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“…Chronic treatment with any of the 3 conventional anti-bipolar drugs Li + , carbamazepine or valproic acid decreases mRNA and protein expression of the TRPC1 (Fig. 3), which results in the inhibition of store-operated Ca 2+ entry [70]. This is consistent with observations in platelets and lymphocytes from bipolar patients as well as with outcome of chronic treatment of lymphoblast cell lines derived from such patients with Li + .…”

Section: Trpc1 Channelssupporting

confidence: 79%

Targeting astrocytes in bipolar disorder

Peng

Verkhratsky

2016

Expert Review of Neurotherapeutics

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Astrocytes are homeostatic cells of the central nervous system, which are critical for development and maintenance of synaptic transmission and hence of synaptically connected neuronal ensembles. Astrocytic densities are reduced in bipolar disorder, and therefore deficient astroglial function may contribute to overall disbalance in neurotransmission and to pathological evolution. Classical anti-bipolar drugs (lithium salts, valproic acid and carbamazepine) affect expression of astroglial genes and modify astroglial signalling and homeostatic cascades. Many effects of both antidepressant and anti-bipolar drugs are exerted through regulation of glutamate homeostasis and glutamatergic transmission, through K(+) buffering, through regulation of calcium-dependent phospholipase A2 (that controls metabolism of arachidonic acid) or through Ca(2+) homeostatic and signalling pathways. Sometimes anti-depressant and anti-bipolar drugs exert opposite effects, and some effects on gene expression in drug treated animals are opposite in neurones vs. astrocytes. Changes in the intracellular pH induced by anti-bipolar drugs affect uptake of myo-inositol and thereby signalling via inositoltrisphosphate (InsP3), this being in accord with one of the main theories of mechanism of action for these drugs.

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Mechanisms for L-channel-mediated increase in [Ca2+] and its reduction by anti-bipolar drugs in cultured astrocytes combined with its mRNA expression in freshly isolated cells support the importance of astrocytic L-channels

Cited by 36 publications

References 70 publications

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Chronic Treatment with Anti-bipolar Drugs Down-Regulates Gene Expression of TRPC1 in Neurones

Targeting astrocytes in bipolar disorder

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