Prandial increase of leptin in the brain activates spatial learning and memory  Yutaka Oomura, Shuji Aou, Kouji Fukunaga  Pathophysiology  Volume 17, Issue 2, Pages 119-127 (April 2010) DOI: 10.1016/j.pathophys.2009.04.004 Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 1 Enhancement of Morris water maze performance by the low concentration of leptin and impairment by the high concentration of leptin. Leptin 0.5μg/kg group, n=16, other group, n=20. The shortest swimming time (A) occurred on day 2 in the 50μg/kg leptin group (compared to vehicle group). Swimming time was significantly greater at 500μg/kg than in control on day 2–4. (B) Probe test after withdrawing t a longer time in the goal-area than the vehicle group on probe test (prb.t) day 3 (p<0.05), whereas the 500μg/kg leptin group spent less time than the vehicle group on probe test day 1–3 (p<0.05). *p<0.05 [5]. Pathophysiology 2010 17, 119-127DOI: (10.1016/j.pathophys.2009.04.004) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 2 Leptin effects on LTP in CA1 neurons. (A) Example records of fEPSPs 20min before (pre) and after (post) tetanization. Left, normal Krebs–Ringer, right, 10−12M leptin. Leptin applied for 15min just before tetanization. (B) Percent change of fEPSP amplitudes. Tetanization took place at zero time (see abscissa). Solid horizontal lines, leptin application for 15min. Ordinate, size of fEPSPs as percentage of baseline (100%). Inset, mean size of fEPSPs (as percentage of baseline) following leptin administration; measurements were made over a 10min period (30–40min after tetanization) 10−14, 10−12, 10−10M leptin, n=3; control, n=6. Leptin groups are all significantly different from the controls. **p<0.01 [5]. Pathophysiology 2010 17, 119-127DOI: (10.1016/j.pathophys.2009.04.004) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 3 Effect of leptin on spontaneous mEPSCs in CA1 neurons. (A) and (B) Examples of high sweep records of mEPSC at 5min (a) before, 10min (b) and 35min (c) after 10−12M (n=3) and 10−10M leptin (n=4) application, respectively. Leptin application, 5min. Membrane potential, clamped at −70mV. (C) and (D) Effects of 10−12 and 10−10M leptin on mEPSC amplitudes, respectively. Left, middle and right histograms in (C) and (D) are mean amplitudes for 5min periods just before, from 10 to 15min and from 35 to 40min after leptin application, respectively. Significant increase in mEPSC amplitudes following 10−12M leptin was seen. *p<0.05, **p<0.01 [5]. Pathophysiology 2010 17, 119-127DOI: (10.1016/j.pathophys.2009.04.004) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 4 Effect of leptin on postsynaptic responses induced in a CA1 neuron by electrophoretic application (25nA for 1s) of Quis, GABA and NMDA. (A) and (B) Effect of 10−12 and 10−10M leptin application, respectively. Upper traces in (A) and (B), 10min after recording had stabilized in normal Krebs–Ringer solution. Middle traces in (A) and (B) 10min after 10−12 and 10−10M leptin application, respectively. No observable changes in postsynaptic responses were seen following 10−12M leptin application, whereas suppression of postsynaptic responses to all three transmitters was seen following 10−10M leptin application. Membrane potential (Rp: −65mV) was not changed by application of 10−12M leptin, but a 5mV depolarization (depol) occurred following 10−10M leptin application. Lower traces in (A) and (B), 10 and 17min after washout, respectively [5]. Pathophysiology 2010 17, 119-127DOI: (10.1016/j.pathophys.2009.04.004) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 5 Increased [Ca2+]i in CA 1 neurons following leptin application. (A) [Ca2+]i in a single CA1 neuron. Upper solid lines, two applications of leptin, each for 10min. Vertical broken line, beginning of exposure to leptin. (B) Increase in mean [Ca2+]i induced by 10−12 and 10−10M leptin (n=6 for each group). *p<0.05 between 10−12 and 10−10M leptin [5]. Pathophysiology 2010 17, 119-127DOI: (10.1016/j.pathophys.2009.04.004) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 6 Recordings of CA1 fEPSP before and after tetanic stimulation in two slices each from different Zucker fatty rats (upper two figures); and three slices from different db/db mice (lower three figures). Tetanic stimulation (100Hz, for 1s) was delivered at time 0 (see abscissa). Each point in the plot shows the fEPSP as a percentage of the initial control (evoked in normal Krebs–Ringer solution). No LTP occurred and no effect of leptin on fEPSPs [11]. Pathophysiology 2010 17, 119-127DOI: (10.1016/j.pathophys.2009.04.004) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 7 Intracellular postsynaptic responses induced by electrophoretic application of Quis, GABA and NMDA in CA1 neuron (recorded from a slice from a Zucker fatty rat). Resting membrane potential, −51mV: (a) in normal Krebs–Ringer solution; (b) in 10−10M leptin (none of the responses was changed by leptin; (c) after washing by normal Krebs–Ringer solution; (d) during hyperpolarization induced by application of −30pA in normal Krebs–Ringer solution, all responses were increased in amplitude [11]. Pathophysiology 2010 17, 119-127DOI: (10.1016/j.pathophys.2009.04.004) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 8 Performance in the Morris water maze test. Left, Zucker fatty rats. Right, db/db mice. (A) Longer swimming distance of Zucker (n=10) and db/db (n=6) than controls (n=6). (B) Probe test. Each left two columns, fewer crossing of original platform location (shadow) than in control (white). Each right two columns, no intergroup difference in time spent in goal area. *p<0.05, **p<0.01 versus control strain [11]. Pathophysiology 2010 17, 119-127DOI: (10.1016/j.pathophys.2009.04.004) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 9 Deduced physiological action of endogenous satiety substance, leptin. Leptin released into plasma during food intake from the adipocytes enters into the brain only by 1/5000 of the plasma concentration. Leptin reaches the glucose-sensitive neurons in the LHA and the medial part of the arcuate nucleus (feeding related centers) and the glucoreceptor neurons in the ventromedial nucleus and lateral part of the arcuate nucleus (satiety related centers) and inhibits feeding. Then leptin reaches the hippocampus and facilitates spatial learning and memory. Leptin reaches the neurons in the parvocellular part of the paraventricular nucleus (pPVN) and activates these neurons causing CRH release. These neurons and CRH activates efferent sympathetic outflow and pituitary–adrenal axis. Splenic sympathetic activation and released corticosterone modulate immune function. Pathophysiology 2010 17, 119-127DOI: (10.1016/j.pathophys.2009.04.004) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions