Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABAA and mGlu receptor subtypes

Vinkers, Christiaan H.; Hendriksen, Erik; Oorschot, Ruud van; Cook, James M.; Rallipalli, Sundari; Huang, Shengming; Millan, Mark J.; Olivier, Berend; Groenink, Lucianne

doi:10.1007/s00213-011-2423-0

Cited by 8 publications

(4 citation statements)

References 62 publications

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“…Within the BLA, it appears that the CRF system and GABAergic systems modulate each other. CRF overexpression leads to changes in GABA receptor subtype expression and sensitivity (Vinkers et al, ). GABAergic disinhibition or CRF excitation both result in increased excitability of neurons within the amygdala (Sajdyk, Schober, Gehlert, & Shekhar, ).…”

Section: Discussionmentioning

confidence: 99%

Distribution of type I corticotropin‐releasing factor (CRF1) receptors on GABAergic neurons within the basolateral amygdala

Calakos

Blackman

Schulz

et al. 2017

Synapse

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The neuropeptide corticotropin-releasing factor (CRF) plays a critical role in mediating anxiety-like responses to stressors, and dysfunction of the CRF system has been linked to the etiology of several psychiatric disorders. Extra-hypothalamic CRF can also modulate learning and memory formation, including amygdala-dependent learning. The basolateral nucleus of the amygdala (BLA) contains dense concentrations of CRF receptors, yet the distribution of these receptors on specific neuronal subtypes within the BLA has not been characterized. Here, we quantified the expression of CRF receptors on three nonoverlapping classes of GABAergic interneurons: those containing the calcium-binding protein parvalbumin (PV), and those expressing the neuropeptides somatostatin (SOM) or cholecystokinin (CCK). While the majority of PV+ neurons and roughly half of CCK+ neurons expressed CRF receptors, they were expressed to a much lesser extent on SOM+ interneurons. Knowledge of the distribution of CRF receptors within the BLA can provide insight into how manipulations of the CRF system modulate fear and anxiety-like behaviors.

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Section: Discussionmentioning

confidence: 99%

Distribution of type I corticotropin‐releasing factor (CRF1) receptors on GABAergic neurons within the basolateral amygdala

Calakos

Blackman

Schulz

et al. 2017

Synapse

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“…A recent article investigated the effects on GABA and glutamatergic transmission in CRH-OE 2122 [ 74 ]. The study showed that constitutive overexpression of CRH reduced sensitivity to the anxiolytic effects of CRH-R1 antagonists, and GABA A and glutamate receptor agonists in response to stress-induced hypothermia.…”

Section: Genetically Altered Rodent Modelsmentioning

confidence: 99%

“…The study showed that constitutive overexpression of CRH reduced sensitivity to the anxiolytic effects of CRH-R1 antagonists, and GABA A and glutamate receptor agonists in response to stress-induced hypothermia. Additionally, mRNA levels of distinct subunits of the GABA A receptors and mGluR 2/3 receptor were differentially altered in amygdala versus the hypothalamus [ 74 ]. The data supports the notion that an imbalance in GABAergic and glutamatergic transmission may underlie the genesis of stress-related maladaptive behaviors.…”

Section: Genetically Altered Rodent Modelsmentioning

confidence: 99%

Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders

Laryea

Arnett

Muglia

2012

Behavioral Sciences

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To maintain well-being, all organisms require the ability to re-establish homeostasis in the presence of adverse physiological or psychological experiences. The regulation of the hypothalamic-pituitary adrenal (HPA) axis during stress is important in preventing maladaptive responses that may increase susceptibility to affective disorders. Corticotropin-releasing hormone (CRH) is a central stress hormone in the HPA axis pathway and has been implicated in stress-induced psychiatric disorders, reproductive and cardiac function, as well as energy metabolism. In the context of psychiatric disorders, CRH dysfunction is associated with the occurrence of post-traumatic stress disorder, major depression, anorexia nervosa, and anxiety disorders. Here, we review the synthesis, molecular signaling and regulation, as well as synaptic activity of CRH. We go on to summarize studies of altered CRH signaling in mutant animal models. This assembled data demonstrate an important role for CRH in neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation. Next, we present findings regarding human genetic polymorphisms in CRH pathway genes that are associated with stress and psychiatric disorders. Finally, we discuss a role for regulators of CRH activity as potential sites for therapeutic intervention aimed at treating maladaptive behaviors associated with stress.

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“…CRF administration increases GABA release within the amygdala (7,8) and causes deficits in GABA(A) receptor-mediated inhibitory transmission (9). Lifelong CRF overexpression leads to changes in GABA receptor subtype expression and sensitivity (10). Furthermore, GABAergic disinhibition or CRF excitation leads to long-term synaptic plasticity and increased excitability of neurons within the amygdala (11,12).…”

mentioning

confidence: 99%

Cell-type specific deletion of GABA(A)α1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction

Gafford

Guo

Flandreau

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Corticotropin-releasing factor (CRF) is critical for the endocrine, autonomic, and behavioral responses to stressors, and it has been shown to modulate fear and anxiety. The CRF receptor is widely expressed across a variety of cell types, impeding progress toward understanding the contribution of specific CRF-containing neurons to fear dysregulation. We used a unique CRF-Cre driver transgenic mouse line to remove floxed GABA(A)α1 subunits specifically from CRF neurons [CRF-GABA(A)α1 KO]. This process resulted in mice with decreased GABA(A)α1 expression only in CRF neurons and increased CRF mRNA within the amygdala, bed nucleus of the stria terminalis (BNST) and paraventricular nucleus of the hypothalamus. These mice show normal locomotor and pain responses and no difference in depressive-like behavior or Pavlovian fear conditioning. However, CRF-GABA(A)α1 KO increased anxiety-like behavior and impaired extinction of conditioned fear, coincident with an increase in plasma corticosterone concentration. These behavioral impairments were rescued with systemic or BNST infusion of the CRF antagonist R121919. Infusion of Zolpidem, a GABA(A)α1-preferring benzodiazepine-site agonist, into the BNST of the CRF-GABA(A)α1 KO was ineffective at decreasing anxiety. Electrophysiological findings suggest a disruption in inhibitory current may play a role in these changes. These data indicate that disturbance of CRF containing GABA(A)α1 neurons causes increased anxiety and impaired fear extinction, both of which are symptoms diagnostic for anxiety disorders, such as posttraumatic stress disorder.central amygdala | plasticity | HPA axis | short term synaptic depression | knockout T he neuropeptide corticotrophin-releasing factor (CRF) is involved in initiation of the endocrine, autonomic, and behavioral responses to stressors and its dysfunction is implicated in a variety of mood and anxiety disorders (1). Large populations of CRF-containing neurons are located within brain areas crucial for fear and anxiety, including the central amygdala (CeA), bed nucleus of the stria terminalis (BNST), and paraventricular nucleus of the hypothalamus (PVN). Although site-specific and conditional knockout approaches are increasingly being used (2, 3), the broad expression of CRF receptors and the varied cell types in which the CRF peptide is produced (4, 5) make it challenging to identify region and cell-type specific influences of CRF. One way to manipulate specific subpopulations of CRF neurons is to use mice with the Cre recombinase gene driven by the CRF promoter to allow different subgroups of CRFergic cells to be manipulated.The interaction between CRF and GABA activity in brain structures important for fear and anxiety has been identified as a potential mechanism underlying anxiety disorders (6). CRF administration increases GABA release within the amygdala (7, 8) and causes deficits in GABA(A) receptor-mediated inhibitory transmission (9). Lifelong CRF overexpression leads to changes in GABA receptor subtype expression and sensitivity (1...

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Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABAA and mGlu receptor subtypes

Cited by 8 publications

References 62 publications

Distribution of type I corticotropin‐releasing factor (CRF1) receptors on GABAergic neurons within the basolateral amygdala

Distribution of type I corticotropin‐releasing factor (CRF1) receptors on GABAergic neurons within the basolateral amygdala

Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders

Cell-type specific deletion of GABA(A)α1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction

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