Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus

• Published in: The European journal of neuroscience 2004-09, Vol.20 (6), p.1665-1673
• Main Authors: Verkuyl, J. Martin, Hemby, Scott E., Joëls, Marian
• Format: Article
• Language: English
• Subjects: 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology; Animals; Blotting, Northern - methods; Body Weight - physiology; Chronic Disease; corticosterone; Dose-Response Relationship, Radiation; Electric Stimulation - methods; evoked response; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; gamma-Aminobutyric Acid - metabolism; Gene Expression - physiology; Hypothalamus - cytology; In Vitro Techniques; Male; Membrane Potentials - drug effects; Membrane Potentials - radiation effects; miniature inhibitory postsynaptic current; N-Methylaspartate - pharmacology; Neural Inhibition - physiology; Neurons - metabolism; Organ Size - physiology; Patch-Clamp Techniques - methods; Rats; Rats, Wistar; Receptors, GABA - classification; Receptors, GABA - genetics; Receptors, GABA - metabolism; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - biosynthesis; single cell RNA amplification; Stress, Physiological - metabolism; Stress, Physiological - physiopathology; Time Factors; whole cell voltage clamp
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2004.03568.x

Chronic stress causes disinhibition of the hypothalamus–pituitary–adrenal axis. Consequently, the brain is overexposed to glucocorticoids which in humans may precipitate stress‐related disorders, e.g. depression. The hypothalamus–pituitary–adrenal activity is strongly regulated by GABAergic input to parvocellular neurons in the hypothalamic paraventricular nucleus. We here report a reduced frequency of miniature inhibitory postsynaptic currents (mIPSCs) in parvocellular neurons of rats exposed to 3 weeks of unpredictable stress. The mIPSC amplitude and kinetic properties were unchanged, pointing to a presynaptic change caused by chronic stress. Because paired‐pulse inhibition was unaffected by chronic stress, the number of functional GABAergic synaptic contacts rather than the release probability seems to be reduced after chronic stress. Linearly amplified RNA from postsynaptic cells was hybridized with multiple cDNA clones of interest, including most GABAA receptor subunits. In agreement with the electrophysiological observations, relative expression of the prevalent GABAAα1, α3, γ1 and γ2 receptor subunits, which largely contribute to the recorded responses, was not altered after chronic stress. However, expression of the extra‐synaptic GABAAα5 subunit, earlier linked to depression in humans, and of the δ receptor subunit were found to be significantly changed. In conclusion, chronic stress leads to presynaptic functional alterations in GABAergic input to the paraventricular nucleus which could contribute to the observed disinhibition of the hypothalamus–pituitary–adrenal axis; additionally other aspects of GABAergic transmission may also be changed due to transcriptional regulation of specific receptor subunits in the parvocellular neurons.