Corticotropin-Releasing Factor Facilitates Epileptiform Activity in the Entorhinal Cortex: Roles of CRF2 Receptors and PKA Pathway

Abstract

Whereas corticotropin-releasing factor (CRF) has been considered as the most potent epileptogenic neuropeptide in the brain, its action site and underlying mechanisms in epilepsy have not been determined. Here, we found that the entorhinal cortex (EC) expresses high level of CRF and CRF2 receptors without expression of CRF1 receptors. Bath application of CRF concentration-dependently increased the frequency of picrotoxin (PTX)-induced epileptiform activity recorded from layer III of the EC in entorhinal slices although CRF alone did not elicit epileptiform activity. CRF facilitated the induction of epileptiform activity in the presence of subthreshold concentration of PTX which normally would not elicit epileptiform activity. Bath application of the inhibitor for CRF-binding proteins, CRF6-33, also increased the frequency of PTX-induced epileptiform activity suggesting that endogenously released CRF is involved in epileptogenesis. CRF-induced facilitation of epileptiform activity was mediated via CRF2 receptors because pharmacological antagonism and knockout of CRF2 receptors blocked the facilitatory effects of CRF on epileptiform activity. Application of the adenylyl cyclase (AC) inhibitors blocked CRF-induced facilitation of epileptiform activity and elevation of intracellular cyclic AMP (cAMP) level by application of the AC activators or phosphodiesterase inhibitor increased the frequency of PTX-induced epileptiform activity, demonstrating that CRF-induced increases in epileptiform activity are mediated by an increase in intracellular cAMP. However, application of selective protein kinase A (PKA) inhibitors reduced, not completely blocked CRF-induced enhancement of epileptiform activity suggesting that PKA is only partially required. Our results provide a novel cellular and molecular mechanism whereby CRF modulates epilepsy.

Expression and function of the metabotropic purinergic P2Y receptor family in experimental seizure models and patients with drug‐refractory epilepsy

“…On the other hand, Gi signaling inhibits adenylate cyclase, thereby decreasing cAMP production and PKA activation . Again, in good agreement with protective mechanisms driving P2Y expression, elevated cAMP has been reported to be proepileptogenic and PKA inhibition reduced epileptiform activity …”

Roles of K+ and cation channels in ORL-1 receptor-mediated depression of neuronal excitability and epileptic activities in the medial entorhinal cortex

“…Because the EC is an important structure involved in epilepsy, we studied the roles of NOP in epilepsy by bath perfusion of PTX or Mg 2+ -free extracellular solution in entorhinal slices. As demonstrated previously (Kurada et al, 2014;Wang et al, 2013), stable epileptiform activity could be recorded from layer III of the EC in the horizontal slices after perfusion of PTX (100 μM) for ~20 min. After recordings of stable basal epileptiform activity for 10 min, NOP (0.3 μM) dissolved in the PTX-containing extracellular solution was applied to the slices for ~ 7 min.…”

The Effects of Psychological Stress on Depression

“…CRF exerts its physiological function by binding to its G-protein coupled receptors, CRF 1 and CRF 2 , to activate the downstream cAMP signaling [ 31 , 45 ]. CRF 1 receptors are highly expressed in the pituitary and the limbic areas where they modulate the activity of HPA axis [ 46 ].…”