Synaptic physiology of central CRH system

Abstract

Corticotropin-Releasing Hormone (CRH) or Corticotropin-Releasing Factor (CRF) and its family of related naturally occurring endogenous peptides and receptors are becoming recognized for their actions within central (CNS) and peripheral (PNS) nervous systems. It should be recognized that the term 'CRH' has been displaced by 'CRF' [Guillemin, R., 2005. Hypothalamic hormones a.k.a. hypothalamic releasing factors. J. Endocrinol. 184, 11-28]. However, to maintain uniformity among contributions to this special issue we have used the original term, CRH. The term 'CRF' has been associated recently with CRH receptors and designated with subscripts by the IUPHAR nomenclature committee [Hauger, R.L., Grigoriadis, D.E., Dallman, M.F., Plotsky, P.M., Vale, W.W., Dautzenberg, F.M., 2003. International Union of Pharmacology. XXXVI. Corticotrophin-releasing factor and their ligands. Pharmacol. Rev. 55, 21-26] to denote the type and subtype of receptors activated or antagonized by CRH ligands. CRH, as a hormone, has long been identified as the regulator of basal and stress-induced ACTH release within the hypothalamo-pituitary-adrenal axis (HPA axis). But the concept, that CRH and its related endogenous peptides and receptor ligands have non-HPA axis actions to regulate CNS synaptic transmission outside the HPA axis, is just beginning to be recognized and identified [Orozco-Cabal, L., Pollandt, S., Liu, J., Shinnick-Gallagher, P., Gallagher, J.P., 2006a. Regulation of Synaptic Transmission by CRF Receptors. Rev. Neurosci. 17, 279-307; Orozco-Cabal, L., Pollandt, S., Liu, J., Vergara, L., Shinnick-Gallagher, P., Gallagher, J.P., 2006b. A novel rat medial prefrontal cortical slice preparation to investigate synaptic transmission from amygdala to layer V prelimbic pyramidal neurons. J. Neurosci. Methods 151, 148-158] is especially noteworthy since this synapse has become a prime focus for a variety of mental diseases, e.g. schizophrenia [Fischbach, G.D., 2007. NRG1 and synaptic function in the CNS. Neuron 54, 497-497], and neurological disorders, e.g., Alzheimer's disease [Bell, K.F., Cuello, C.A., 2006. Altered synaptic function in Alzheimer's disease. Eur. J. Pharmacol. 545, 11-21]. We suggest that "The Stressed Synapse" has been overlooked [c.f., Kim, J.J., Diamond, D.M. 2002. The stressed hippocampus, synaptic plasticity and lost memories. Nat. Rev., Neurosci. 3, 453-462; Radley, J.J., Morrison, J.H., 2005. Repeated stress and structural plasticity in the brain. Ageing Res. Rev. 4, 271-287] as a major contributor to many CNS disorders. We present data demonstrating CRH neuroregulatory and neuromodulatory actions at three limbic synapses, the basolateral amygdala to central amygdala synapse; the basolateral amygdala to medial prefrontal cortex synapse, and the lateral septum mediolateral nucleus synapse. A novel stress circuit is presented involving these three synapses. We suggest that CRH ligands and their receptors are significant etiological factors that need to be considered in the pharmacotherapy of mental diseases associated with CNS synaptic transmission.

Fig. 1. Roles for CRH, CRH Receptor (CRHR) Ligands as Neuroregulators (‘Primers’) within CNS Synapses

Tonic role of endogenous CRH as demonstrated following application of a CRH receptor antagonist results in an enhancement or depression of the primary transmitter’s action, e.g., upon glutamate transmission at central amygdala nucleus or lateral septum mediolateral nucleus synapses; OR, Phasic role of CRH acting either by evoked or volume transmission to modulate the action of a principal transmitter, e.g., glutamate; or, a modulator, e.g., enhance dopamine’s affects on basolateral amygdala to medial prefrontal cortex glutamatergic synaptic transmission.

Fig. 2

Distribution and regulatory functions depicted for CRH₁ and CRH₂ synaptic receptors upon excitatory synaptic transmission, [facilitatory-light gray and depressant-dark grey]. CRH₁ and CRH₂ receptors regulate glutamatergic transmission within synapses in the central amygdala nucleus, Left, and lateral septum medial lateral nucleus, Right. R\hCRF and Ucn I (Urocortin I), CRH₁ and CRH₂ receptor agonists, respectively –each produce opposite effects to inhibit or facilitate excitatory transmission-monitored as excitatory postsynaptic currents (EPSCs)-in the two different limbic nuclei, central amygdala nucleus and lateral septum mediolateral nucleus. Note low nanomolar effective concentrations. Adapted From: J. Neurosci.,24, 4020–4029.

Fig. 3

Following chronic cocaine administrations and its withdrawal there are changes in sensitivities and functions of CRH and Ucn 1 within the lateral septal mediolateral nucleus. CRH₁ receptor mediated facilitation of glutamatergic transmission persists, albeit CRH is less potent compared to control, whereas the former CRH₂-mediated depression by Ucn 1 is switched to facilitation, and at comparable potency. Diagram depicts receptor distributions and functions before and after chronic cocaine at lateral septum mediolateral nucleus synapse. Adapted From: J. Neurosci.,25, 577–583.

Fig. 4

Switch in dopamine and CRH actions after acute withdrawal from chronic cocaine. A. In saline control slices D1-like activation (SKF 81297) inhibited excitatory postsynaptic current (EPSC) amplitude; SKF 81297 effects were enhanced by addition of CRH at a concentration of CRH that did not itself affect basolateral amygdala-medial prefrontal cortex EPSCs. B. After acute withdrawal from chronic cocaine, SKF 81297 and CRH synergistically enhanced EPSC amplitude at medial prefrontal cortex synapses. Comparable results to SKF 81297 obtained with dopamine.

Fig. 5

Diagram depicting a novel stress network [medial prefrontal cortex ↔ amygdala ↔ septum] implicating CRH AND DOPAMINE (DA) as regulator and modulator of excitatory synaptic transmission (glutamate -GLUT) between these three nuclei, and other major limbic nuclei. Facilitatory or depressant regulatory roles of CRH upon excitatory glutamatergic transmission under control conditions at two of the three synapses (#a=basolateral nucleus (BLA) to central amygdala nucleus (CeA); #b=central amygdala nucleus (CeA) to lateral septum mediolateral nucleus (LSMLN) are depicted as (+) or (−), respectively. At basolateral amygdala nucleus (BLA) to medial prefrontal cortex (mPFC), synapse #c, and under control conditions CRH does not regulate glutamatergic transmission (0), but rather modulates positively (+) the depressant action of dopamine upon glutamatergic transmission.

Fig. 6

Long-Term Potentiation (LTP) in basolateral amygdala-central amygdala nucleus pathway (Fig. 5,#a) is dependent on CRF₁ receptors in saline and cocaine-treated preparations. A.,B. Orthodromic stimulation of basolateral amygdala-central amygdala nucleus pathway with high frequency stimulation (HFS) induced LTP in saline-treated animals (Left) or chronic cocaine treated animals (Right). HFS-LTP is blocked by selective CRF₁ antagonist (NBI27914, 250 nM) in both preparations. NOTE: Higher magnitude LTP in brains from cocaine-treated animals (Right).