Acute rapamycin rescues the hyperexcitable phenotype of accumbal medium spiny neurons in the valproic acid rat model of autism spectrum disorder

Iezzi, Daniela; Curti, Lorenzo; Ranieri, Giuseppe; Gerace, E; Costa, Alessia; Ilari, A; Rocca, A La; Luceri, C; D’Ambrosio, M; Silvestri, L; Scardigli, M; Mannaioni, Guido; Masi, Alessio

doi:10.1016/j.phrs.2022.106401

Cited by 4 publications

(4 citation statements)

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“…Rapamycin is FDA approved and has been proven to benefit both AD and epilepsy models 14,114,115 . While rapalogs may affect numerous signaling pathways downstream of mTORC1 to attenuate disease course, including autophagy and neuroinflammation 116,117 , growing evidence demonstrates efficacy in regulating neuronal hyperexcitability [53][54][55][56][57][58] . In the studies presented here, rapamycin reduced NKCC1/KCC2 and GluA1/GluA2 ratios in PTZ kindled 5XFAD mice and showed a trend to increase GABAARa1/GABAARa3 in non-kindled 5XFAD mice, suggesting reversal of seizure-exacerbated E:I imbalance, which may indicate restoration of proper circuitry involved in memory in these mice 14 .…”

Section: Discussionmentioning

confidence: 99%

“…Further, PTZ kindling exacerbated the imbalance in both excitatory and inhibitory markers. Rapamycin treatment has been shown to rescue neuronal hyperexcitability in various disease models [53][54][55][56][57][58] . Thus, we sought to determine whether chronic low-dose rapamycin treatment beginning at the cessation of PTZ kindling (prodromal stage ~4 months, 2.24 mg/kg daily), previously used to rescue seizure-induced neuropathology and cognitive deficits in 5XFAD mice 14 , could ameliorate PTZ-exacerbated E:I imbalance.…”

Section: Kindling During the Prodromal Stage Alters The Progressive A...mentioning

confidence: 99%

“…Studies of models of Tuberous Sclerosis Complex, characterized by constitutive mTORC1 overactivation commonly resulting in epilepsy 51,52 , have demonstrated that blockade of mTORC1 with rapamycin can rescue GABAergic neurotransmission and epilepsy [53][54][55][56] . Rapamycin treatment has also rescued neuronal hyperexcitability in models of autism spectrum disorder 57 and neuropathic pain 58 . Together, these results indicate that targeting mTORC1 activity might restore E:I balance across multiple disease models, including AD.…”

Section: Introductionmentioning

confidence: 99%

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Excitatory: inhibitory imbalance in Alzheimer’s disease is exacerbated by seizures with attenuation after rapamycin treatment in 5XFAD mice

Barbour

Gourmaud

et al. 2023

Preprint

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Increasing evidence indicates a bidirectional relationship between epilepsy and Alzheimer’s disease (AD) with 22% of AD patients additionally suffering from seizures, which may be a targetable component of disease progression. Since epileptogenesis is associated with changes in excitatory: inhibitory (E:I) balance, we examined postmortem AD brain tissue from patients with and without seizure history and five times familial AD (5XFAD) mice for changes in several markers of E:I balance, including the inhibitory GABAAreceptor, the chloride cotransporters, sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2), and the excitatory NMDA and AMPA type glutamate receptors. We hypothesized that seizure history in AD patients would be associated with greater E:I imbalances, and that such changes would also be observed in the 5XFAD mice following pentylenetetrazol (PTZ) kindling. We found that seizures in AD patients were associated with alterations in NKCC1 and KCC2 expression, indicative of depolarizing GABA, and exacerbated cognitive deficits. Seizures also significantly contributed to E:I imbalance in the 5XFAD mouse model, as similar changes in NKCC1 and KCC2 expression were found in PTZ treated 5XFAD mice, along with altered AMPA receptor protein expression indicative of calcium permeable-AMPA receptors. In addition, we found that chronic treatment with the mTOR inhibitor rapamycin at doses we have previously shown to attenuate seizure-inducedβ-amyloid pathology and cognitive deficits in 5XFAD mice, can mitigate the dysregulation of markers of E:I balance in this model. These data suggest that mTOR activation plays a role in modifying the E:I imbalance and network hyperexcitability in AD and that the FDA-approved mTOR inhibitors such as rapamycin may have potential for therapy in AD patients with a seizure history.

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Section: Discussionmentioning

confidence: 99%

Section: Kindling During the Prodromal Stage Alters The Progressive A...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Excitatory: inhibitory imbalance in Alzheimer’s disease is exacerbated by seizures with attenuation after rapamycin treatment in 5XFAD mice

Barbour

Gourmaud

et al. 2023

Preprint

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“…Importantly, impaired mTORC1 signaling has been implicated in ASD and related neurodevelopmental disorders [ 69 , 74 – 76 ], consistent with the success of rapamycin treatment in rescuing social behavior deficits in ASD mouse models [ 77 – 79 ]. Rapamycin treatment was shown to reverse cellular [ 78 , 80 ], synaptic [ 63 , 81 – 83 ], and behavioral [ 63 , 78 , 80 , 81 , 83 – 87 ] deficits in genetic, idiopathic and environmental ASD rodent models. However, rapamycin has not been successful in rescuing behavioral abnormalities in the Fmr1 knockout mice, worsening social interaction deficits and impairing sleep duration [ 88 ], or in rescuing the repetitive behavioral deficits in Tsc1 mutant mice [ 78 , 80 , 89 ].…”

Section: Introductionmentioning

confidence: 99%

Maturation of nucleus accumbens synaptic transmission signals a critical period for the rescue of social deficits in a mouse model of autism spectrum disorder

et al. 2023

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Social behavior emerges early in development, a time marked by the onset of neurodevelopmental disorders featuring social deficits, including autism spectrum disorder (ASD). Although social deficits are at the core of the clinical diagnosis of ASD, very little is known about their neural correlates at the time of clinical onset. The nucleus accumbens (NAc), a brain region extensively implicated in social behavior, undergoes synaptic, cellular and molecular alterations in early life, and is particularly affected in ASD mouse models. To explore a link between the maturation of the NAc and neurodevelopmental deficits in social behavior, we compared spontaneous synaptic transmission in NAc shell medium spiny neurons (MSNs) between the highly social C57BL/6J and the idiopathic ASD mouse model BTBR T+Itpr3tf/J at postnatal day (P) 4, P6, P8, P12, P15, P21 and P30. BTBR NAc MSNs display increased spontaneous excitatory transmission during the first postnatal week, and increased inhibition across the first, second and fourth postnatal weeks, suggesting accelerated maturation of excitatory and inhibitory synaptic inputs compared to C57BL/6J mice. BTBR mice also show increased optically evoked medial prefrontal cortex-NAc paired pulse ratios at P15 and P30. These early changes in synaptic transmission are consistent with a potential critical period, which could maximize the efficacy of rescue interventions. To test this, we treated BTBR mice in either early life (P4-P8) or adulthood (P60-P64) with the mTORC1 antagonist rapamycin, a well-established intervention for ASD-like behavior. Rapamycin treatment rescued social interaction deficits in BTBR mice when injected in infancy, but did not affect social interaction in adulthood.

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Inhibition of purinergic P2 receptors prevents synaptic and behavioral alterations in a rodent model of autism spectrum disorders.

Babiec,

Wilkaniec,

Gawinek

et al. 2024

Research in Autism Spectrum Disorders

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Acute rapamycin rescues the hyperexcitable phenotype of accumbal medium spiny neurons in the valproic acid rat model of autism spectrum disorder

Cited by 4 publications

References 58 publications

Excitatory: inhibitory imbalance in Alzheimer’s disease is exacerbated by seizures with attenuation after rapamycin treatment in 5XFAD mice

Excitatory: inhibitory imbalance in Alzheimer’s disease is exacerbated by seizures with attenuation after rapamycin treatment in 5XFAD mice

Maturation of nucleus accumbens synaptic transmission signals a critical period for the rescue of social deficits in a mouse model of autism spectrum disorder

Inhibition of purinergic P2 receptors prevents synaptic and behavioral alterations in a rodent model of autism spectrum disorders.

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