Metabotropic glutamate receptor subtype 7 ablation causes dysregulation of the HPA axis and increases hippocampal BDNF protein levels: implications for stress-related psychiatric disorders.
Regulation of neurotransmission via group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) has recently been implicated in the pathophysiology of affective disorders, such as major depression and anxiety. For instance, mice with a targeted deletion of the gene for mGluR7 (mGluR7-/-) showed antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Deletion of mGluR7 reduces also amygdala- and hippocampus-dependent conditioned fear and aversion responses. Since the hypothalamic-pituitary-adrenal (HPA) axis regulates the stress response we investigate whether parameters of the HPA axis at the levels of selected mRNA transcripts and endocrine hormones are altered in mGluR7-deficient mice. Over all, mGluR7-/- mice showed only moderately lower serum levels of corticosterone and ACTH compared with mGluR7+/+ mice. More strikingly however, we found strong evidence for upregulated glucocorticoid receptor (GR)-dependent feedback suppression of the HPA axis in mice with mGluR7 deficiency: (i) mRNA transcripts of GR were significantly upregulated in the hippocampus of mGluR7-/- animals, (ii) similar increases were seen with 5-HT1A receptor transcripts, which are thought to be directly controlled by the transcription factor GR and finally (iii) mGluR7-/- mice showed elevated sensitivity to dexamethasone-induced suppression of serum corticosterone when compared with mGluR7+/+ animals. These results indicate that mGluR7 deficiency causes dysregulation of HPA axis parameters, which may account, at least in part, for the phenotype of mGluR7-/- mice in animal models for anxiety and depression. In addition, we present evidence that protein levels of brain-derived neurotrophic factor are also elevated in the hippocampus of mGluR7-/- mice, which we discuss in the context of the antidepressant-like phenotype found in those animals. We conclude that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in affective disorders.
Mitsukawa
Kayo
K
Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
Mombereau
Cedric
C
Lötscher
Erika
E
Uzunov
Doncho P
DP
van der Putten
Herman
H
Flor
Peter J
PJ
Cryan
John F
JF
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D007118:Immunoassay / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay / Q000379:methods; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013312:Stress, Physiological / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D044282:Receptor, Serotonin, 5-HT1A; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone