mTOR is essential for corticosteroid effects on hippocampal AMPA receptor function and fear memory

Abstract

Glucocorticoid hormones, via activation of their receptors, promote memory consolidation, but the exact underlying mechanisms remain elusive. We examined how corticosterone regulates AMPA receptors (AMPARs), which are crucial for synaptic plasticity and memory formation. Combining a live imaging fluorescent recovery after photobleaching approach with the use of the pH-sensitive GFP-AMPAR tagging revealed that corticosterone enhances the AMPAR mobile fraction and increases synaptic trapping of AMPARs in hippocampal cells. In parallel, corticosterone-enhanced AMPARmediated synaptic transmission. Blocking the mammalian target of rapamycin (mTOR) pathway prevented the effects of corticosterone on both AMPAR trapping-but not on the mobile fraction-and synaptic transmission. Blocking the mTOR pathway also prevented the memory enhancing effects of corticosterone in a contextual fear-conditioning paradigm. We conclude that activation of the mTOR pathway is essential for the effects of corticosterone on synaptic trapping of AMPARs and, possibly as a consequence, fearful memory formation.

Effects of corticosterone on mild auditory fear conditioning and extinction; role of sex and training paradigm

“…Numerous studies have illustrated that glucocorticoids facilitate memory consolidation (e.g., Pugh et al 1997a;Sandi and Rose 1997;Roozendaal 2000Roozendaal , 2002de Quervain et al 2009;Xiong et al 2015). Also in the current study, we find that corticosterone increases memory consolidation.…”

“…All experimental procedures occurred in the morning between 09.00 a.m. and 11.00 a.m. During testing, the mice were recorded by a camera connected to a computer with Ethovision software (version 6.1, Noldus). Mice were placed in a square chamber with black walls (W × L × H: 30 × 24 × 26 cm) which had a stainless steel grid floor connected to a shock generator (Zhou et al 2010;Xiong et al 2015), and which had been cleaned with 1% acidic acid to create a recognizable odor trace. Mice were allowed to explore the context for 3 min, after which once or three times, a 30-sec tone was applied (2.8 kHz, 76 dB), coupled to a 2-sec footshock (0.1, 0.2, or 0.4 mA) during the last 2 sec of the tone, with an inter-tone-interval of 60 sec (the "training" phase) (see Fig.…”

Glucocorticoid and β‐adrenergic regulation of hippocampal dendritic spines

“…Primary hippocampal cultures were prepared from Wistar rat brains at embryonic day 18 ± 1, as described previously . Briefly, hippocampi were dissected and homogenised, and cells were plated on 12 mm coverslips coated with poly‐ d ‐lysine (0.5 mg mL ‐1 ) at a density of 75 000 neurons/coverslip.…”

“…mEPSCs were recorded at a holding potential of −70 mV . Tetrodotoxin (0.25 µmol L ‐1 ; Latoxan, Portes lès Valence, France) and bicuculline methobromide (20 µmol L ‐1 ; Biomol, Hamburg, Germany) were added to the buffer to block action potential induced glutamate release and GABA‐A receptor‐mediated miniature inhibitory postsynaptic currents, respectively.…”

“…At the cellular level, GC effects involve rapid changes in glutamatergic synaptic transmission, including enhanced neurotransmitter release and alterations in AMPA and NMDA receptor mobility . More slowly, corticosterone enhances glutamatergic (AMPA and NMDA receptor‐mediated) synaptic transmission, which underlies enhanced memory formation . In addition, various lines of evidence indicate that glucocorticoids also enhance spine formation, which are critical for learning and memory …”