-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance.
Bartosz Kula, Botond Antal, Corey Weistuch, Florian Gackière, Alexander Barre, Victor Velado, Jeffrey M Hubbard, Maria Kukley, Lilianne R Mujica-Parodi, Nathan A Smith
Author Information
Bartosz Kula: Del Monte Institute for Neuroscience, Department of Neuroscience, University of Rochester, School of Medicine and Dentistry, Rochester, USA.
Botond Antal: Department of Biomedical Engineering, Stony Brook University, Stony Brook, USA.
Corey Weistuch: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Florian Gackière: Neuroservices Alliance, Les Jardins de l'Entreprise, Quartier de le Confrérie, Le Puy Ste Réparade, France.
Alexander Barre: Neuroservices Alliance, Les Jardins de l'Entreprise, Quartier de le Confrérie, Le Puy Ste Réparade, France.
Victor Velado: Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington D.C., USA.
Jeffrey M Hubbard: Neuroservices Alliance, Les Jardins de l'Entreprise, Quartier de le Confrérie, Le Puy Ste Réparade, France.
Maria Kukley: Achucarro Basque Center for Neuroscience, Leioa, Spain.
Lilianne R Mujica-Parodi: Department of Biomedical Engineering, Stony Brook University, Stony Brook, USA. ORCID
Nathan A Smith: Del Monte Institute for Neuroscience, Department of Neuroscience, University of Rochester, School of Medicine and Dentistry, Rochester, USA. ORCID
The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely on glucose transporter 4 (GLUT4) or insulin, has shown promising clinical applicability in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of exogenous KB D-β-hydroxybutyrate (D-βHb) on mouse brain metabolism during acute insulin resistance (AIR). We found that both AIR and D-βHb had distinct impacts across neuronal compartments: AIR decreased synaptic activity and long-term potentiation (LTP) and impaired axonal conduction, synchronization, and action potential (AP) properties, while D-βHb rescued neuronal functions associated with axonal conduction, synchronization, and LTP.
