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Dopamine and Glutamate Crosstalk Worsen the Seizure Outcome in TLE-HS Patients

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Abstract

Temporal lobe epilepsy (TLE), accompanied by hippocampal sclerosis (HS), is the most common form of drug-resistant epilepsy (DRE). Nearly 20% of the patients showed seizure recurrence even after surgery, and the reasons are yet to be understood. Dysregulation of neurotransmitters is evident during seizures, which can induce excitotoxicity. The present study focused on understanding the molecular changes associated with Dopamine (DA) and glutamate signaling and their possible impact on the persistence of excitotoxicity and seizure recurrence in patients with drug-resistant TLE-HS who underwent surgery. According to the International League against Epilepsy (ILAE) suggested classification for seizure outcomes, the patients (n = 26) were classified as class 1 (no seizures) and class 2 (persistent seizures) using the latest post-surgery follow-up data to understand the prevalent molecular changes in seizure-free and seizure-recurrence patient groups. Our study uses thioflavin T assay, western blot analysis, immunofluorescence assays, and fluorescence resonance energy transfer (FRET) assays. We have observed a substantial increase in the DA and glutamate receptors that promote excitotoxicity. Patients who had seizure recurrence showed a significant increase in (pNR2B, p < 0.009; and pGluR1, p < 0.01), protein phosphatase1γ (PP1γ; p < 0.009), protein kinase A (PKAc; p < 0.001) and dopamine-cAMP regulated phospho protein32 (pDARPP32T34; p < 0.009) which are critical for long-term potentiation (LTP), excitotoxicity compared to seizure-free patients and controls. A significant increase in D1R downstream kinases like PKA (p < 0.001), pCAMKII (p < 0.009), and Fyn (p < 0.001) was observed in patient samples compared to controls. Anti-epileptic DA receptor D2R was found to be decreased in ILAE class 2 (p < 0.02) compared to class 1. Since upregulation of DA and glutamate signaling supports LTP and excitotoxicity, we believe it could impact seizure recurrence. Further studies about the impact of DA and glutamate signaling on the distribution of PP1γ at postsynaptic density and synaptic strength could help us understand the seizure microenvironment in patients.

Graphical Abstract

Dopamine, Glutamate signal crosstalk. Diagram representing the PP1γ regulation by NMDAR negative feedback inhibition signaling (green circle-left) and D1R signal (red circle-middle) domination over PP1γ though increased PKA, pDARPP32T34, and supports pGluR1, pNR2B in seizure recurrent patients. D1R-D2R hetero dimer activation (red circle-right) increases cellular Ca2+ and pCAMKIIα activation. All these events lead to calcium overload in HS patients and excitotoxicity, particularly in patients experiencing recurrent seizures.

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All the data provided in the manuscript and original data supplied as a supplementary file.

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Acknowledgements

Human Brain Tissue Repository for Neurobiological Studies, Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India, provided the autopsied control brain samples for this study. Krishna Institute of Medical Sciences (KIMS), also the KIMS research foundation (KFRC), and Dr. Sailaja Department of Pathology, Krishna Institute of Medical Science, Secunderabad, India for technical assistance with data collection. The financial assistance from the Department of Science and Technology, Government of India, DST- SERB Core grant, file Nos. CRG/2020/005021, CRG/2019/002570, and financial support to the University of Hyderabad-IoE by the Ministry of Education, Government of India (F11/9/2019-U3 (A). DST-FIST, and UGC-SAP to the Department of Biotechnology and Bioinformatics, BUILDER-DBT-BT/INF/22/SP41176/2020 to the School of Life Sciences is gratefully acknowledged. Kishore Madamanchi is thankful to CSIR-UGC Fellowship under Ref. no: 22/12/2013(II)EU-V (341059).

Funding

The financial assistance to the lab from the Ministry of Science and Technology, Department of Science and Technology, Govt. of India, DST- SERB Core grant, file No. CRG/2020/005021; DST-CSRI files No. SR/CSRI/196/2016, CRG/2020/005021; Department of Biotechnology, Govt. of India, BT/PR18168/MED/29/1064/2016, BT/PR17686/MED/30/1664/ 2016, and financial support to the University of Hyderabad-IoE by the Ministry of Education, Govt. of India (F11/9/2019-U3 (A) DST-FIST and UGC-SAP for the department.

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  1. Pradeep Madhamanchi

    Present address: Govt. Degree College for Men’s, Srikakulam District, Andhra Pradesh, 532001, India

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  1. Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, 500046, India

    Kishore Madhamanchi, Pradeep Madhamanchi & Prakash Babu Phanithi

  2. Department of Neurology, Krishna Institute of Medical Sciences (KIMS), Secunderabad, Telangana, India

    Sita Jayalakshmi, Manas Panigrahi & Anuja Patil

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Contributions

All the authors contributed to the study concept. The work plan was designed by [Prof. Prakash Babu Phanithi]. Data collection and data processing performed by [Kishore Madhamanchi]. Tissue sample and data collection by [Pradeep Madhamanchi]. Epilepsy surgery, storage of patient samples, and individual patient data provided by [Manas Panigrahi, Sita Jayalakshmi, and Anuja Patil. The first draft of the manuscript was prepared by [Kishore Madhamanchi] Corresponding author, and all authors commented on the previous version. All the authors read and approved the final manuscript.

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Correspondence to Prakash Babu Phanithi.

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Madhamanchi, K., Madhamanchi, P., Jayalakshmi, S. et al. Dopamine and Glutamate Crosstalk Worsen the Seizure Outcome in TLE-HS Patients. Mol Neurobiol 60, 4952–4965 (2023). https://doi.org/10.1007/s12035-023-03361-4

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