FGF2 blocks PTSD symptoms via an astrocyte-based mechanism

1. FGF2 blocks PTSD symptoms via an astrocyte-based mechanism Presented by Justin P. Smith

2. FGF2 • Growth factor, protein or steroid hormone, that regulating cell proliferation, differentiation, and survival • 22 FGF ligands • 4 FGF receptors in rodents, • 5 FGF receptors in humans • Single chain polypeptide protein • FGF2 has contributed significantly: • Mechanisms neuronal proliferation, survival, and repair

3. Roles of FGF2 • Alter structure of hippocampus • regulating cell proliferation, morphology • increasing synaptic efficiency • modulates several of the molecules in LTP and memory • formation and/or consolidation of extinction memories • Other roles?

5. Fibroblast Growth Factor-2 Enhances Extinction and ReducesRenewal of Conditioned Fear • Conditioned Fear • CS- white noise; level in the chambers was increased by 8 dB during CS • US- 0.6 mA, 1.0 s footshock • FGF2, subcutaneously after the last extinction trial • Renewal-extinguished CS is presented in the original fear conditioning context, or in a completely novel context, the animal will express recovered levels of fear

6. Fig. 1: FGF2 facilitates long-term extinction and needs to be administered at a dose no less than 20 ng/g of body weight to be effective

7. Fig. 2: FGF2 significantly reduced renewal after extinction, even when the levels of CS-elicited freezing in the vehicle and FGF2-treated rats tested in the extinction context were equated

8. Fig. 3: FGF2 significantly reduced renewal after extinction even when the time spent in the extinction context was equated between FGF2- and vehicle-treated rats • FGF2 may change quality of extinction, • possibly weakening the original fear memory

9. Main Paper Intro • Cellular mechanism for PTSD not fully understood • Role of astrocytes in mood disorders • Largest population in hippocampus • FGF2 • Synthesized in astrocytes • Modulates adult rat hippocampal neurogenesis • enhances long-term extinction of fear memory &reduces reinstatement

10. Methods • ♂ Sprague-Dawley rats (180-200g) • 12:12 light dark (lights off at?) • Single Prolonged Stress (SPS) • 1) restrained for 2 h • 2) 20 min forced swimming • 15-min recuperation • 3) ether exposure until general anesthesia (<5 min)

11. Behavioral Tests • Open Field (OF) • Elevated Plus Maze (EPM) • Conditioned Fear

12. Brain Regions Anterior Cingulate Cortex-reward anticipation, decision-making, impulse control, and emotion

14. Fig. 2 • FGF2 ↓ enhanced fear response in the conditioned fear extinction and sensitized fear tests • CS+: test for conditioned fear response to shock chamber; • CSn: test for sensitized fear response to neutral tone in a neutral context

15. Fig. 3: OF Fig. 3 Open Field

16. Fig. 4 EPM

17. Fig. 5: • SPS inhibited the astrocytic action • FGF2 application from SPS day 7 to 10 activated GFAP immunodensities to normal levels

18. Fig. 6: 3-D reconstruction of FGF2 on GFAP expression in hippocampus induced by SPS

19. Fig. 7 Effects of i.p. admin of FGF2 on GFAP and NeuN expression in hippocampus of SPS rats

20. Take home • GFAP ↓ in SPS • FGF2 rescue effect • ↓ Anxiety and freezing behavior • FGF2 possible therapeutic for PTSD • Astrocyte role in PTSD • Astrocytes may be underlying the mechanisms of PTSD?!?