Journal Article

Stress-induced modulation of endocannabinoid signaling leads to delayed strengthening of synaptic connectivity in the amygdala

Teskey, G. Campbell, van der Stelt, Mario, Chattarji, Sumantra, Hill, Matthew N., Pittman, Quentin J., McEwen, Bruce S., Morena, Maria, Colangeli, Roberto, Hillard, Cecilia J., Yasmin, Farhana, Filipski, Sarah

2020

Overview

Even a brief exposure to severe stress strengthens synaptic connectivity days later in the amygdala, a brain area implicated in the affective symptoms of stress-related psychiatric disorders. However, little is known about the synaptic signaling mechanisms during stress that eventually culminate in its delayed impact on the amygdala. Hence, we investigated early stress-induced changes in amygdalar synaptic signaling in order to prevent its delayed effects. Whole-cell recordings in basolateral amygdala (BLA) slices from rats revealed higher frequency of miniature excitatory postsynaptic currents (mEPSCs) immediately after 2-h immobilization stress. This was replicated by inhibition of cannabinoid receptors (CB₁R), suggesting a role for endocannabinoid (eCB) signaling. Stress also reduced N-arachidonoylethanolamine (AEA), an endogenous ligand of CB₁R. Since stress-induced activation of fatty acid amide hydrolase (FAAH) reduces AEA, we confirmed that oral administration of an FAAH inhibitor during stress prevents the increase in synaptic excitation in the BLA soon after stress. Although stress also caused an immediate reduction in synaptic inhibition, this was not prevented by FAAH inhibition. Strikingly, FAAH inhibition during the traumatic stressor was also effective 10 d later on the delayed manifestation of synaptic strengthening in BLA neurons, preventing both enhanced mEPSC frequency and increased dendritic spine-density. Thus, oral administration of an FAAH inhibitor during a brief stress prevents the early synaptic changes that eventually build up to hyperexcitability in the amygdala. This framework is of therapeutic relevance because of growing interest in targeting eCB signaling to prevent the gradual development of emotional symptoms and underlying amygdalar dysfunction triggered by traumatic stress.

• Publisher: National Academy of Sciences
• Subject: Administration, Oral / Amidohydrolases - antagonists & inhibitors / Amidohydrolases - metabolism / Amygdala / Anandamide / Animals / Basolateral Nuclear Complex - physiology / Biological Sciences / Cannabinoid CB1 receptors / Cannabinoid Receptor Antagonists - administration & dosage / Dendritic spines / Disease Models, Animal / Emotions - drug effects / Emotions - physiology / Endocannabinoids - metabolism / Enzyme Inhibitors - administration & dosage / Excitatory postsynaptic potentials / Excitatory Postsynaptic Potentials - drug effects / Excitatory Postsynaptic Potentials - physiology / Fatty acids / Fatty-acid amide hydrolase / Humans / Hydrolase / Immobilization / Inhibition (psychology) / Inhibitors / Male / Mental disorders / Neural networks / Neuroscience / Oral administration / Rats / Receptor, Cannabinoid, CB1 - antagonists & inhibitors / Receptor, Cannabinoid, CB1 - metabolism / Receptors / Signal Transduction - drug effects / Signal Transduction - physiology / Signaling / Signs and symptoms / Spine / Stress / Stress, Psychological - drug therapy / Stress, Psychological - physiopathology / Stress, Psychological - psychology