Group II metabotropic glutamate receptors in anxiety circuitry: correspondence of physiological response and subcellular distribution.
Activation of group II metabotropic glutamate receptors (mGluR2/3) in the amygdala plays a critical role in the regulation of fear and anxiety states. Previous studies using nonselective agonists have suggested this action can result from activation of either pre- or postsynaptic mGluR2/3. Here, we have used a combination of whole-cell patch clamp recording with highly selective agonists (LY354740 and LY379268) and immunoelectron microscopy to examine structure-function relationships for mGluR2/3 in the basolateral amygdala (BLA) and bed nucleus of the stria terminalis (BNST). Stimulation of mGluR2/3 evoked a direct, TTX-insensitive membrane hyperpolarization in all BLA projection neurons tested, but only about half of BNST neurons. The membrane hyperpolarization was mediated by activation of an outward potassium current or blockade of a tonically active inward I(h) current in different groups of BLA neurons. In both regions, mGluR2/3 caused a long-lasting reduction of glutamate release from presynaptic afferent terminals even at concentrations that failed to elicit a direct postsynaptic response. The localization of mGluR2/3 differed regionally, with postsynaptic labeling significantly more common in BLA than BNST, corresponding to the strength of postsynaptic responses recorded there. Our results demonstrate a complex role for mGluR2/3 receptors in modulating anxiety circuitry, including direct inhibition and reduction of excitatory drive. The combination of direct inhibition of projection neurons within the BLA and suppression of excitatory neurotransmission in the BNST may be responsible for the anxiolytic actions of group II mGluR agonists.
Muly
E Chris
EC
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30329, USA. ecmuly@rmy.emory.edu
Mania
Irakli
I
Guo
Ji-Dong
JD
Rainnie
Donald G
DG
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D001008:Anxiety Disorders / Q000378:metabolism / Q000503:physiopathology; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016253:Microscopy, Immunoelectron; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D018690:Excitatory Amino Acid Agonists; D015221:Potassium Channels; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D018698:Glutamic Acid