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GABAergic Interneuron and Neurotransmission Are mTOR-Dependently Disturbed in Experimental Focal Cortical Dysplasia

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Abstract

Focal cortical dysplasia (FCD) is a major cause for drug-resistant epilepsies. The molecular and cellular mechanisms of epileptogenesis in FCD are still poorly understood. Some studies have suggested that deficiencies of γ-aminobutyric acid (GABA) system may play an important role in type II FCD, but it remains controversial. In order to examine whether and how GABAergic interneurons and synaptic function are affected, we generated a somatic mTOR hyperactivation-based mouse model of type II FCD by in utero electroporation, quantified densities of interneurons in the malformed cortices, and recorded miniature inhibitory postsynaptic currents in dysmorphic neurons. We detected 20–25% reduction of GABAergic interneurons within malformed cortices, independent of cortical regions and cell subtypes but proportionate to the decrease of global neuron counts. GABAergic synaptic transmission from interneurons to mTOR hyperactivated dysmorphic neurons was dramatically disrupted, outweighing the decrease of interneuron counts. Postnatal mTOR inhibition partially rescued these alterations of GABAergic system. We also quantified the expression of GABAA receptor, GABA transporter, and chloridion transporter encoding genes and found that their expression was relatively intact within the malformed cortices. Taken together, these results confirmed that GABAergic interneuron and synapse transmission are disturbed profoundly in an mTOR-dependent manner in type II FCD. Our study suggests that postsynaptic mechanisms independent of interneuron reduction or altered expression of GABA synapse genes might be accountable for the impaired GABAergic neurotransmission in type II FCD as well as other mTOR-related epilepsies.

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Abbreviations

GABA:

γ-Aminobutyric acid

FCD:

Focal cortical dysplasia

mTOR:

Mechanistic target of rapamycin

mIPSC:

Miniature inhibitory postsynaptic current

IUE:

In utero electroporation

RT-PCR:

Real-time polymerase chain reaction

GFP:

Green fluorescent protein

GAD:

Glutamate decarboxylase

PV:

Parvalbumin

SST:

Somatostatin

CR:

Calretinin

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Acknowledgments

We are grateful to Professor Yunli Xie (Fudan University) for the generous gift of pCAG-GFP plasmid.

Funding

This work was funded by project grants from the National Natural Science Foundation of China (Code: 81771308,31771184).

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Authors and Affiliations

  1. Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China

    Shaoping Zhong, Wanjing Xie, Yiying Cai, Yiying Zhang, Jing Ding & Xin Wang

  2. Department of The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China

    Zhihao Zhao & Xin Wang

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  1. Shaoping Zhong
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Zhong, S., Zhao, Z., Xie, W. et al. GABAergic Interneuron and Neurotransmission Are mTOR-Dependently Disturbed in Experimental Focal Cortical Dysplasia. Mol Neurobiol 58, 156–169 (2021). https://doi.org/10.1007/s12035-020-02086-y

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