FGF2 blocks PTSD symptoms via an astrocyte-based mechanism

Presented by Justin P. Smith

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

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?

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

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

Fig. 2: FGF2 significantly reduced renewal afterextinction, even when the levels of CS-elicited freezing inthe vehicle and FGF2-treated rats tested in the extinctioncontext were equated

Fig. 3: FGF2 significantly reduced renewal after extinction evenwhen the time spent in the extinction context was equatedbetween FGF2- and vehicle-treated rats

•FGF2 may change quality of extinction, possibly weakening the original fear memory

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

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)

Behavioral Tests

• Open Field (OF)• Elevated Plus Maze (EPM)• Conditioned Fear

Brain Regions

Anterior Cingulate Cortex-reward anticipation, decision-making, impulse control, and emotion

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

Fig. 3 Open FieldFig. 3: OF

Fig. 4 EPM

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

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

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

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?!?