GSK3β Modulates Timing-Dependent Long-Term Depression Through Direct Phosphorylation of Kv4.2 Channels

Aceto, Giuseppe; Re, Agnese; Mattera, Andrea; Leone, Lucia; Colussi, Claudia; Rinaudo, Marco; Scala, Federico; Gironi, Katia; Barbati, Saviana Antonella; Fusco, Salvatore; Green, Thomas; Laezza, Fernanda; D’Ascenzo, Marcello; Grassi, Claudio

doi:10.1093/cercor/bhy042

Cited by 9 publications

(14 citation statements)

References 108 publications

(155 reference statements)

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“…Notably, Ser-616 lies in a putative GSK3β consensus motif. Recent evidence indicates that if phosphorylated by GSK3β, Ser-616 promotes decreased A-type K + channel activity in layer 2/3 of the somatosensory cortex (38), confirming that Ser-616 is a converging site of multiple kinase signaling mechanisms.…”

Section: Discussionmentioning

confidence: 92%

“…Slice Preparation and Electrophysiology. Coronal slices (300 μm) containing the NAc were prepared as previously described (38). Recordings were performed using the MultiClamp 700B/Digidata 1550A System (Molecular Devices) digitized at a 10,000-Hz sampling frequency.…”

Section: Methodsmentioning

confidence: 99%

“…We next sought to identify the molecular mechanism downstream of GSK3β underlying the STDP modulation we observed in CUMS-treated mice. In a recent study, we demonstrated a functional interaction between GSK3β and voltage-gated potassium Kv4.2 channels, molecular determinants of A-type K + currents, as a novel mechanism for synaptic plasticity modulation in layer 2/3 pyramidal neurons of the somatosensory cortex (38). As A-type K + currents are critical for dendritic and synaptic processing during synaptic plasticity (48), we hypothesized that GSK3β-dependent inhibition of Kv4.2 channels in mice exposed to CUMS would lead to broadened dendritic backpropagation, increased Ca 2+ influx during the pairing protocol, and, as a consequence, increased tLTP.…”

Section: Knockdown Of Gsk3β In the Nac Shell Ameliorates Depressive-likementioning

confidence: 99%

“…We then hypothesized that knocking down GSK3β in NAc MSNs would counteract the increased tLTP in mice exposed to CUMS. To test our hypothesis, we used in vivo genetic silencing by injecting an adeno-associated viral vector (AAV2) short hairpin RNA against mouse GSK3β (AAV-shGSK3β-GFP [green fluorescent protein]) into the NAc shell of adult mice (37,38). AAV-shCTRL-GFP not targeting any known mouse transcripts was used as control (37).…”

Section: Cums Treatment Affects Timing-dependent Ltp In Shell Accumbensmentioning

confidence: 99%

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Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels

Aceto

Colussi

Leone

et al. 2020

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

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Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3β in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3β in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3β. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K+currents, as a potential downstream target of GSK3β. We found increased levels of active GSK3β and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3β knockdown. Furthermore, knockdown of GSK3β in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3β-dependent tLTP changes in CUMS mice. Our results identify GSK3β regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3β–Kv4.2 axis may be an attractive therapeutic target for MDD.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Knockdown Of Gsk3β In the Nac Shell Ameliorates Depressive-likementioning

confidence: 99%

Section: Cums Treatment Affects Timing-dependent Ltp In Shell Accumbensmentioning

confidence: 99%

See 2 more Smart Citations

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels

Aceto

Colussi

Leone

et al. 2020

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

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“…Over 500 substrates have been predicted for GSK3 [51], 50 of which are protein targets in the CNS [19,26]. Only recently, though, voltage-gated ion channels such as voltage-gated Na + (Na v ) [52,53] and voltage-gated K + (K v ) [54][55][56] channels have emerged as GSK3β substrates [34,57]. Herein, we provide an overview of the mechanisms by which GSK3β mediates direct and indirect effects on Na v and K v channels with implications for neuronal excitability, plasticity, and ultimately vulnerability to neuropsychiatric disorders [34,53,56,58,59].…”

Section: Introductionmentioning

confidence: 99%

Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases

Marosi

Arman

Aceto

et al. 2022

IJMS

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Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na+ channels (Nav1.2 and Nav1.6) and voltage-gated K+ channels (Kv4 and Kv7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.

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Glycine-induced activation of GPR158 increases the intrinsic excitability of medium spiny neurons in the nucleus accumbens

Aceto,

Nardella,

Nanni

et al. 2024

Cell. Mol. Life Sci.

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It has been recently established that GPR158, a class C orphan G protein-coupled receptor, serves as a metabotropic glycine receptor. GPR158 is highly expressed in the nucleus accumbens (NAc), a major input structure of the basal ganglia that integrates information from cortical and subcortical structures to mediate goal-directed behaviors. However, whether glycine modulates neuronal activity in the NAc through GPR158 activation has not been investigated yet. Using whole-cell patch-clamp recordings, we found that glycine-dependent activation of GPR158 increased the firing rate of NAc medium spiny neurons (MSNs) while it failed to significantly affect the excitability of cholinergic interneurons (CIN). In MSNs GPR158 activation reduced the latency to fire, increased the action potential half-width, and reduced action potential afterhyperpolarization, effects that are all consistent with negative modulation of potassium M-currents, that in the central nervous system are mainly carried out by Kv7/KCNQ-channels. Indeed, we found that the GPR158-induced increase in MSN excitability was associated with decreased M-current amplitude, and selective pharmacological inhibition of the M-current mimicked and occluded the effects of GPR158 activation. In addition, when the protein kinase A (PKA) or extracellular signal-regulated kinase (ERK) signaling was pharmacologically blocked, modulation of MSN excitability by GPR158 activation was suppressed. Moreover, GPR158 activation increased the phosphorylation of ERK and Kv7.2 serine residues. Collectively, our findings suggest that GPR158/PKA/ERK signaling controls MSN excitability via Kv7.2 modulation. Glycine-dependent activation of GPR158 may significantly affect MSN firing in vivo, thus potentially mediating specific aspects of goal-induced behaviors.

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GSK3β Modulates Timing-Dependent Long-Term Depression Through Direct Phosphorylation of Kv4.2 Channels

Cited by 9 publications

References 108 publications

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels

Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases

Glycine-induced activation of GPR158 increases the intrinsic excitability of medium spiny neurons in the nucleus accumbens

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