Stress-Induced Endocannabinoid Signalling Affects Amygdala Synaptic Connectivity

Post by Flora Moujaes

What's the science? 

Post-Traumatic Stress Disorder (PTSD) is a debilitating condition usually triggered by a traumatic event, that typically consists of (1) re-experiencing the traumatic event though intrusive memories and flashbacks, and (2) a state of constant vigilance or hyperactivity. We know that PTSD has a delayed onset, and that its often accompanied by hyperactivity in the amygdala - a brain region that plays a key role in the processing of emotions. Research has shown that a brief exposure to severe stress strengthens synaptic connectivity 10 days later in the amygdala, but we still don’t know what signalling mechanism is responsible for the delayed changes. Recently, there has been a huge surge in the number of patients with PTSD self-medicating using cannabis. This has led to the hypothesis that abnormal endocannabinoid signalling may be involved in the amygdala dysfunction seen in PTSD. This week in PNAS, Yasmin and colleagues investigate for the first time whether administering a pharmacological substance that modulates endocannabinoid signalling can prevent the impact of acute stress on the amygdala of rats.  

How did they do it?

To explore the mechanisms by which stress results in synaptic changes in the amygdala, researchers subjected rats to 2 hours of stress plastic immobilization bags, which contained a slit to allow animals to breathe, but no food or water. Amygdala slices were obtained 15 mins after the end of the stress exposure. They used whole-cell recordings in amygdala slices to first determine the effect of stress on the amygdala. Then, to investigate the involvement of the endocannabinoid signalling system they examined the effect of stress on the amygdala after inhibiting cannabinoid receptors. Next, they investigated the endocannabinoid signalling system more closely, focusing on how stress affects it’s two ligands (a neurochemical substance that binds to receptors): 1) N-arachidonylethanolamine (AEA) and 2) 2-arachidonoylglycerol (2-AG). In particular, they investigated how stress reduces AEA. Finally, they examined the effect of orally administering a substance that indirectly halts the reduction of AEA during stress exposure. 

What did they find?

The researchers showed that stress caused immediate synaptic changes in the amygdala, as evidenced by a higher frequency of miniature excitatory postsynaptic currents (mEPSC). They also found that pharmacologically inhibiting cannabinoid receptors resulted in similar synaptic changes in the amygdala, which indicates that the endocannabinoid signalling system is crucial to the amygdala dysfunction seen following stress. When the researchers then investigated how the specific ligands involved in the endocannabinoid signalling system were affected by stress, they found that stress resulted in reduced AEA. Finally, they showed that orally administering a substance (a fatty acid amide hydrolase (FAAH) inhibitor) that indirectly halts the reduction of AEA during the stress exposure, prevented the synaptic excitability in the amygdala of rats. Most strikingly, FAAH inhibition during the stress exposure was also effective 10 days later, preventing both the enhanced mEPSC frequency and the increased dendritic spine-density usually seen following stress.

What's the impact? 

The oral administration of a pharmacological compound that elevates the levels of an endogenous cannabinoid receptor ligand during stress, can prevent the early synaptic changes that eventually lead up to hyper-excitability in the amygdala. This finding has direct clinical relevance, as hyperactivity of the amygdala is a hallmark finding in PTSD. It suggests that the inhibition of FAAH could act as a novel treatment approach for PTSD, as FAAH inhibition could be used to target the endocannabinoid signalling system to prevent the gradual development of amygdala dysfunction triggered by traumatic stress.

Yasmin et al. Stress-induced modulation of endocannabinoid signaling leads to delayed strengthening of synaptic connectivity in the amygdala. PNAS (2019). Access the original scientific publication here.