TY - JOUR
T1 - Loss of leptin-induced modulation of hippocampal synaptic trasmission and signal transduction in high-fat diet-fed mice
AU - Mainardi, Marco
AU - Spinelli, Matteo
AU - Scala, Federico
AU - Mattera, Andrea
AU - Fusco, Salvatore
AU - D'Ascenzo, Marcello
AU - Grassi, Claudio
PY - 2017
Y1 - 2017
N2 - Hippocampal plasticity is triggered by a variety of stimuli including sensory inputs, neurotrophins and inflammation. Leptin, whose primary function is to regulate food intake and energy expenditure, has been recently shown to affect hippocampal neurogenesis and plasticity. Interestingly, mice fed a high-fat diet (HFD) exhibit impaired hippocampal function, but the underlying mechanisms are poorly understood. To address this issue, we compared leptin responsiveness of hippocampal neurons in control and HFD-fed mice by combining single-cell electrophysiology and biochemical assays. We found that leptin modulated spontaneous and evoked synaptic transmission in control, but not HFD, mice. This functional impairment was paralleled by blunted activation of STAT-3, one of the key signal transduction pathways controlled by the fully functional isoform of the leptin receptor, ObRb. In addition, SOCS-3 expression was non-responsive to leptin, indicating that modulation of negative feedback impinging on ObRb was also altered. Our results advance the understanding of leptin action on hippocampal plasticity and, more importantly, suggest that leptin resistance is a key determinant of hippocampal dysfunction associated with hypercaloric diet.
AB - Hippocampal plasticity is triggered by a variety of stimuli including sensory inputs, neurotrophins and inflammation. Leptin, whose primary function is to regulate food intake and energy expenditure, has been recently shown to affect hippocampal neurogenesis and plasticity. Interestingly, mice fed a high-fat diet (HFD) exhibit impaired hippocampal function, but the underlying mechanisms are poorly understood. To address this issue, we compared leptin responsiveness of hippocampal neurons in control and HFD-fed mice by combining single-cell electrophysiology and biochemical assays. We found that leptin modulated spontaneous and evoked synaptic transmission in control, but not HFD, mice. This functional impairment was paralleled by blunted activation of STAT-3, one of the key signal transduction pathways controlled by the fully functional isoform of the leptin receptor, ObRb. In addition, SOCS-3 expression was non-responsive to leptin, indicating that modulation of negative feedback impinging on ObRb was also altered. Our results advance the understanding of leptin action on hippocampal plasticity and, more importantly, suggest that leptin resistance is a key determinant of hippocampal dysfunction associated with hypercaloric diet.
KW - CA1
KW - Cellular and Molecular Neuroscience
KW - ObR
KW - Patch-clamp
KW - SOCS-3
KW - STAT-3
KW - Schaffer collateral
KW - CA1
KW - Cellular and Molecular Neuroscience
KW - ObR
KW - Patch-clamp
KW - SOCS-3
KW - STAT-3
KW - Schaffer collateral
UR - http://hdl.handle.net/10807/106314
UR - http://journal.frontiersin.org/article/10.3389/fncel.2017.00225/full
U2 - 10.3389/fncel.2017.00225
DO - 10.3389/fncel.2017.00225
M3 - Article
SN - 1662-5102
VL - 2017
SP - N/A-N/A
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
ER -