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GABAergic deficits in absence of LPA1 receptor, associated anxiety-like and coping behaviors, and amelioration by interneuron precursor transplants into the dorsal hippocampus

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Abstract

Defects in GABAergic function can cause anxiety- and depression-like behaviors among other neuropsychiatric disorders. Therapeutic strategies using the transplantation of GABAergic interneuron progenitors derived from the medial ganglionic eminence (MGE) into the adult hippocampus reversed the symptomatology in multiple rodent models of interneuron-related pathologies. In turn, the lysophosphatidic acid receptor LPA1 has been reported to be essential for hippocampal function. Converging evidence suggests that deficits in LPA1 receptor signaling represent a core feature underlying comparable hippocampal dysfunction and behaviors manifested in common neuropsychiatric conditions. Here, we first analyzed the GABAergic interneurons in the hippocampus of wild-type and maLPA1-null mice, lacking the LPA1 receptor. Our data revealed a reduction in the number of neurons expressing GABA, calcium-binding proteins, and neuropeptides such as somatostatin and neuropeptide Y in the hippocampus of maLPA1-null mice. Then, we used interneuron precursor transplants to test links between hippocampal GABAergic interneuron deficit, cell-based therapy, and LPA1 receptor-dependent psychiatric disease-like phenotypes. For this purpose, we transplanted MGE-derived interneuron precursors into the adult hippocampus of maLPA1-null mice, to test their effects on GABAergic deficit and behavioral symptoms associated with the absence of the LPA1 receptor. Transplant studies in maLPA1-null mice showed that grafted cells were able to restore the hippocampal host environment, decrease the anxiety-like behaviors and neutralize passive coping, with no abnormal effects on motor activity. Furthermore, grafted MGE-derived cells maintained their normal differentiation program. These findings reinforce the use of cell-based strategies for brain disorders and suggest that the LPA1 receptor represents a potential target for interneuron-related neuropsychiatric disorders.

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Acknowledgements

We gratefully acknowledge IBIMA joint support structures for research (ECAI). Likewise, we are obliged to the staff of the animal housing and central research facilities at Universidad de Málaga and CABIMER. Finally, we appreciate the services from American Journal Experts (Durham, NC, USA) for English Language Editing.

Funding

This work was supported by grants from the Spanish Ministry of Science, Innovation and Universities, co-funded by the European Regional Development Fund (ERDF, EU), (PSI2017-82604R, to LJS; PSI2017-83408-P to CP; SAF09-07746, to MAD; PI16/01510, to GET) and Andalusian Regional Ministries of Economy, Knowledge, Business and University (SEJ-4515 -to LJS; SEJ1863 to CP) and of Health and Families (Nicolas Monardes Programme to GET).

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Author notes

  1. Cristina Rosell-Valle

    Present address: Unidad de Producción de Reprogramación Celular, Red Andaluza Para El Diseño Y Traslación de Terapias Avanzadas, Junta de Andalucía, Spain

  2. Cristina Rosell-Valle and Magdalena Martínez-Losa have contributed equally.

Authors and Affiliations

  1. Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain

    Cristina Rosell-Valle, Elisa Matas-Rico, Estela Castilla-Ortega, Emma Zambrana-Infantes, Ana Isabel Gómez-Conde, Lourdes Sánchez-Salido, David Ladrón de Guevara-Miranda, Carmen Pedraza, Pedro Jesús Serrano-Castro, Fernando Rodríguez de Fonseca, Luis Javier Santín & Guillermo Estivill-Torrús

  2. Unidad Clínica de Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain

    Cristina Rosell-Valle, Pedro Jesús Serrano-Castro & Guillermo Estivill-Torrús

  3. Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Universidad de Málaga, Málaga, Spain

    Cristina Rosell-Valle, Emma Zambrana-Infantes, David Ladrón de Guevara-Miranda, Carmen Pedraza & Luis Javier Santín

  4. Laboratorio de Terapia Celular en Neuropatologías, Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC, Sevilla, Spain

    Magdalena Martínez-Losa & Manuel Álvarez-Dolado

  5. Departamento de Biología Molecular y Bioquímica, Universidad de Málaga, Málaga, Spain

    Elisa Matas-Rico

  6. Unidad Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Málaga, Spain

    Estela Castilla-Ortega & Fernando Rodríguez de Fonseca

  7. ECAI de Microscopía, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain

    Ana Isabel Gómez-Conde & Lourdes Sánchez-Salido

  8. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    Jerold Chun

Authors
  1. Cristina Rosell-Valle
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  2. Magdalena Martínez-Losa
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  3. Elisa Matas-Rico
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  4. Estela Castilla-Ortega
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  5. Emma Zambrana-Infantes
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  6. Ana Isabel Gómez-Conde
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  7. Lourdes Sánchez-Salido
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  8. David Ladrón de Guevara-Miranda
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  9. Carmen Pedraza
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  10. Pedro Jesús Serrano-Castro
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  11. Jerold Chun
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  12. Fernando Rodríguez de Fonseca
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  13. Manuel Álvarez-Dolado
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  14. Luis Javier Santín
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  15. Guillermo Estivill-Torrús
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Contributions

Conceptualization, CRV, MML, EMR, GET, LJS, and MAD; Methodology, CRV, MML; EMR, ECO, LSS, DLGM, AIGC, EZI, and CP; Investigation, interpretation, CRV, MML, EZI, CP, JC and MAD; Project Administration, LJS, MAD and GET.; Supervision, LJS, MAD and GET; Funding Acquisition and Resources, MAD, LJS, FRF, PJSC; Writing-Original Draft, CRV and GET.

Corresponding author

Correspondence to Guillermo Estivill-Torrús.

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Conflict of interest

The authors have no conflicts of interest to declare.

Ethics approval

Experiments were conducted in accordance with the European guidelines, according to the Directives of the Council of the European Community 2010/63/EU, 90/219/EEC, and Regulation (EC)nº1946/2003, and to the national laws on laboratory animal welfare (Royal Decrees 53/2013 and 178/2004, Laws 32/2007 and 9/2003 and regional Decree 320/2010), and approved by the Experimentation Ethics Committees of the University of Malaga and CABIMER.

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All authors have directly participated in the planning, execution, or analysis of this study and approved the contents of the manuscript and its submission by the corresponding author.

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Rosell-Valle, C., Martínez-Losa, M., Matas-Rico, E. et al. GABAergic deficits in absence of LPA1 receptor, associated anxiety-like and coping behaviors, and amelioration by interneuron precursor transplants into the dorsal hippocampus. Brain Struct Funct 226, 1479–1495 (2021). https://doi.org/10.1007/s00429-021-02261-4

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