Developmental impaired Akt signaling in the Shank1 and Shank3 double knock-out mice

Mossa, Adele; Pagano, Jessica; Ponzoni, Luisa; Tozzi, Alessandro; Vezzoli, Elena; Sciaccaluga, Miriam; Costa, Cinzia; Beretta, Stefania; Francolini, Maura; Sala, Mariaelvina; Calabresi, Paolo; Boeckers, Tobias M.; Sala, Carlo; Verpelli, Chiara

doi:10.1038/s41380-020-00979-x

Cited by 31 publications

(29 citation statements)

References 56 publications

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“…D The distribution of significant excitatory or inhibitory responses (−1.96 > z-score > 1.96) in all cell-odor pairs from units shown in C differed among the genotypes. E Left, mean baseline firing of all units was decreased in SH-RX mice (data were log-transformed for statistical tests, ANOVA, Dunnett's post-test, p < 0. the first five weeks of life [65]. It also excludes a major direct contribution of transgenic chromosome 12 insertions [23] of the Camk2a-tTA transgene in our behavioral analysis.…”

Section: Discussionmentioning

confidence: 90%

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

et al. 2021

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Mutations in SHANK genes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported in Shank KO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK proteins, but these remain poorly defined. In this study, we examined how SHANK2 can mediate electrophysiological, molecular, and behavioral effects by conditionally overexpressing either wild-type SHANK2A or the extrasynaptic SHANK2A(R462X) variant. SHANK2A overexpression affected pre- and postsynaptic targets and revealed a reversible, development-dependent autism spectrum disorder-like behavior. SHANK2A also mediated redistribution of Ca2+-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, leading to impaired synaptic plasticity in the basal dendrites. Moreover, SHANK2A overexpression reduced social interaction and increased the excitatory noise in the olfactory cortex during odor processing. In contrast, overexpression of the extrasynaptic SHANK2A(R462X) variant did not impair hippocampal synaptic plasticity, but still altered the expression of presynaptic/axonal signaling proteins. We also observed an attention-deficit/hyperactivity-like behavior and improved social interaction along with enhanced signal-to-noise ratio in cortical odor processing. Our results suggest that the disruption of pre- and postsynaptic SHANK2 functions caused by SHANK2 mutations has a strong impact on social behavior. These findings indicate that pre- and postsynaptic SHANK2 actions cooperate for normal neuronal function, and that an imbalance between these functions may lead to different neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 90%

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

et al. 2021

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“…Several data have demonstrated that PI3K/Akt/mTOR signaling plays an important role in synaptic plasticity and may influence neurological excitability (Meng et al, 2013; Mossa et al, 2021; Sharma and Mehan, 2021). It has also been demonstrated that the PI3K/Akt/mTOR pathway is overactivated in different ASD and epilepsy mouse models including the Scn1a+/- mouse model (Xing et al, 2019; Tai et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Rescuing epileptic and behavioral alterations in a Dravet syndrome mouse model by inhibiting eukaryotic eEF2K

Beretta¹,

Ponzoni²,

Gritti³

et al. 2021

Preprint

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Dravet Syndrome is a severe childhood pharmacoresistant epileptic disorder caused mainly by mutations in the SCN1A gene, which encodes for the α1 subunit of the type I voltage-gated sodium channel (NaV1.1), that cause imbalance between excitation and inhibition in the brain. We recently found that eEF2K knock out mice displayed enhanced GABAergic transmission and tonic inhibition and were less susceptible to epileptic seizures. In Scn1a+/- mice, a mouse model of the Dravet syndrome, we found that the activity of eEF2K/eEF2 pathway was enhanced. Then, we demonstrated that both genetic deletion and pharmacological inhibition of eEF2K were able to reduce the epileptic phenotype of Scn1a+/- mice. Interestingly we also found that motor coordination defect, memory impairments, and stereotyped behavior of the Scn1a+/- mice were reverted by eEF2K deletion. The analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) suggested that the rescue of the pathological phenotype was driven by the potentiation of GABAergic synapses. Our data indicate that pharmacological inhibition of eEF2K could represent a novel therapeutic intervention for treating epilepsy and related comorbidities in the Dravet syndrome.

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“…Several data have demonstrated that PI3K/Akt/mTOR signaling plays an important role in synaptic plasticity and may in uence neurological excitability (38)(39)(40). It has also been demonstrated that the PI3K/Akt/mTOR pathway is overactivated in different ASD and epilepsy mouse models including the Scn1a+/mouse model (22,41).…”

Section: Discussionmentioning

confidence: 99%

Rescuing Epileptic and Behavioral Alterations in a Dravet Syndrome Mouse Model by Inhibiting Eukaryotic Elongation Factor 2 Kinase (eEF2K)

Beratta¹,

Ponzoni²,

Gritti³

et al. 2021

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Background: Dravet Syndrome is a severe childhood pharmaco-resistant epileptic disorder mainly caused by mutations in the SCN1A gene, which encodes for the α1 subunit of the type I voltage-gated sodium channel (NaV1.1), that cause imbalance between excitation and inhibition in the brain. We recently found that eEF2K knock out mice displayed enhanced GABAergic transmission and tonic inhibition and were less susceptible to epileptic seizures. Thus, we investigated the effect of inhibition of eEF2K on the epileptic and behavioral phenotype of Scn1a+/- mice, a murine model of Dravet Syndrome.Methods: To elucidate the role of eEF2K pathway in the etiopathology of Dravet syndrome we generated a new mouse model deleting the eEF2K gene in Scn1a+/- mice. By crossing Scn1a+/- mice with eEF2K-/- mice we obtained the three main genotypes needed for our studies, Scn1a+/+eEF2K+/+ (WT mice), Scn1a+/-eEF2K+/+ mice (Scn1a+/- mice) and Scn1a+/-eEF2K-/- mice, that were fully characterized for EEG and behavioral phenotype. Furthermore, we tested the ability of a pharmacological inhibitor of eEF2K in rescuing EEG alterations of the Scn1a+/- mice.Results: We showed that the activity of eEF2K/eEF2 pathway was enhanced in Scn1a+/- mice. Then, we demonstrated that both genetic deletion and pharmacological inhibition of eEF2K were sufficient to ameliorate the epileptic phenotype of Scn1a+/- mice. Interestingly we also found that motor coordination defect, memory impairments, and stereotyped behavior of the Scn1a+/- mice were reverted by eEF2K deletion. The analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) suggested that the rescue of the pathological phenotype was driven by the potentiation of GABAergic synapses. Limitations: Even if we found that eEF2K deletion was able to increase inhibitory synapses function, the molecular mechanism underlining the inhibition of eEF2K/eEF2 pathway in rescuing epileptic and behavioral alterations in the Scn1a+/- needs further investigations.Conclusions: Our data indicate that pharmacological inhibition of eEF2K could represent a novel therapeutic intervention for treating epilepsy and related comorbidities in the Dravet syndrome.

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Developmental impaired Akt signaling in the Shank1 and Shank3 double knock-out mice

Cited by 31 publications

References 56 publications

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

Rescuing epileptic and behavioral alterations in a Dravet syndrome mouse model by inhibiting eukaryotic eEF2K

Rescuing Epileptic and Behavioral Alterations in a Dravet Syndrome Mouse Model by Inhibiting Eukaryotic Elongation Factor 2 Kinase (eEF2K)

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