Decreased Amygdala CRF-Binding Protein mRNA in Post-Mortem Tissue from Male but not Female Bipolar and Schizophrenic Subjects

Abstract

Stressful life events are commonly associated with the onset and maintenance of psychopathology and much research has focused on the role of the corticotropin-releasing factor (CRF) system in mediating psychopathology. Since CRF serves to integrate the stress response, it is possible that the CRF system plays a role as a neurochemical linkage between stress and psychopathology. CRF-binding protein (CRF-BP) is thought to modulate CRF activity by decreasing its actions. Therefore, in some psychopathological states, alterations in CRF-BP function may contribute to dysregulation of the CRF system. Since the amygdala CRF system mediates stress-and anxietyrelated behaviors and alterations in amygdala function are associated with psychopathology, we examined amygdala CRF-BP gene expression in post-mortem brains from subjects with major depression, bipolar disorder, and schizophrenia as well as in controls. In addition to characterizing the anatomic distribution of CRF-BP mRNA in the human amygdala and medial temporal lobe region, we found a significant decrease in CRF-BP mRNA levels in the basolateral amygdala of male bipolar and male schizophrenic subjects and the lateral amygdala of male bipolar subjects. These results raise the possibility that men with decreased amygdala CRF-BP may be more vulnerable to the effects of stress exposure on the etiology or maintenance of bipolar disorder or schizophrenia.

Evidence for the role of corticotropin-releasing factor in major depressive disorder

“…This may be explained, in part, by the down-regulation of cortical CRF 1 (but not CRF 2 ) receptors that is observed in suicide victims (Merali et al, 2004). Noteworthy, a down-regulation of amygdala CRF BP is also observed in patients with bipolar disorder (Herringa et al, 2006). It is clinically significant that elevated plasma CRF levels in depressed individuals are ameliorated with successful electroconvulsive shock therapy (Nemeroff et al, 1991) or antidepressant treatment (De Bellis et al, 1993; Heuser et al, 1998; Holsboer, 2000; Veith et al, 1993).…”

Applications of blood-based protein biomarker strategies in the study of psychiatric disorders

“…The gene for corticotrophin-releasing hormone (CRH) has been shown to be a risk factor for bipolar disorder with genome-wide significance (McQueen et al, 2005) and polymorphisms in the CRH receptor gene (CRHR1) have been associated with childhood maltreatment and proposed as a predictor for recurrent major depressive disorder (Polanczyk et al, 2009). Consistent with alterations in the HPA axis, corticotropin-releasing factor binding protein (CRFBP) mRNA was found to be decreased in the amygdala of bipolar disorder patients (Herringa et al, 2006). Previous studies have shown that cortisol levels are high in major depressive disorder (Gibbons and Mc, 1962) and depressed patients fail to show regular suppression of cortisol release in the dexamethasone test (Carroll, 1982;Pace and Miller, 2009), suggesting HPA axis dysfunction.…”

HPA Axis Modulation in the Treatment of Mood Disorders

“…Its primary function is to bind CRF and Urocortin 1 to reduce their bioavailability and prevent binding to the CRF receptors [53][54]. To our knowledge, CRF-BP has received little attention as a novel therapeutic target for drug development and treatment of mood disorders despite its regulatory function in the HPA system [56].…”