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Competing Interests: Frank G. Rücker reports honoraria from and consultancy for Jazz Pharmaceuticals, Novartis, and BMS/Celgene; travel support from Jazz Pharmaceuticals. Michael Lübbert reports an advisory role for Abbvie, Astex Pharmaceuticals, Imago BioSciences, Janssen, Otsuka, and Syros; research support from Janssen and Cheplapharm. Michael W. M. Kühn reports honoraria from and consultancy for Pfizer, Kura Oncology, Jazz Pharmaceuticals, BMS/Celgene, and Abbvie; speakers bureau of Gilead. Lars Bullinger reports honoraria from Abbvie, Amgen, Astellas, BMS/Celgene, Daiichi Sankyo, Gilead, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Roche, and Sanofi; research support from Bayer and Jazz Pharmaceuticals. Verena I. Gaidzik reports an advisory role for Jazz Pharmaceuticals, Abbvie, and Boehringer‐Ingelheim; speakers bureau of Pfizer, Janssen, and Abbvie; and travel support from Abbvie. Frank Stegelmann reports honoraria from and consultancy for AOP Pharma, MorphoSys, BMS/Celgene, Incyte, Novartis, and Pfizer. Felicitas Thol reports an advisory role for Novartis, BMS, Abbvie, Menarini, and Rigel. Michael Heuser reports honoraria from Certara, Jazz Pharmaceuticals, Janssen, Novartis, and Sobi; paid consultancy for Abbvie, Amgen, BMS/Celgene, Glycostem, LabDelbert, Pfizer, PinotBio, and Servier; and research funding to his institution from Abbvie, Agios, Astellas, BMS/Celgene, Glycostem, Jazz Pharmaceuticals, Karyopharm, Loxo Oncology, and PinotBio. Hartmut Döhner declares being in an advisory role for Abbvie, Agios, Amgen, Astellas, AstraZeneca, Berlin Chemie, BMS/Celgene, Daiichi Sankyo, GEMoaB, Gilead, Janssen, Jazz Pharmaceuticals, Novartis, Servier, Stemline, and Syndax; research funding from Abbvie, Agios, Amgen, Astellas, BMS/Celgene, Jazz Pharmaceuticals, Kronos Bio, Novartis, and Pfizer. Konstanze Döhner reports an advisory role for Amgen, BMS/Celgene, Daiichi Sankyo, Janssen, Jazz Pharmaceuticals, Novartis, and Roche; research funding from Agios, Astex, Astellas, BMS/Celgene, and Novartis. All other authors declare no competing interest. The remaining authors declared no conflicts of interest.

Glutamate is the most important excitatory neurotransmitter in the brain. The ability to assess glutamate release and re-uptake with high spatial and temporal resolution is crucial to understand the involvement of this primary excitatory neurotransmitter in both normal brain function and different neurological disorders. Real-time imaging of glutamate transients by fluorescent nanosensors has been accomplished in rat brain slices. We performed for the first time single-wavelength glutamate nanosensor imaging in human cortical brain slices obtained from patients who underwent epilepsy surgery. The glutamate fluorescence nanosensor signals of the electrically stimulated human cortical brain slices showed steep intensity increase followed by an exponential decrease. The spatial distribution and the time course of the signal were in good agreement with the position of the stimulation electrode and the dynamics of the electrical stimulation, respectively. Pharmacological manipulation of glutamate release and reuptake was associated with corresponding changes in the glutamate fluorescence nanosensor signals. We demonstrated that the recently developed fluorescent nanosensors for glutamate allow to detect neuronal activity in acute human cortical brain slices with high spatiotemporal precision. Future application to tissue samples from different pathologies may provide new insights into pathophysiology without the limitations of an animal model., (© 2022. The Author(s).)