mGluR8 Modulates Excitatory Transmission in the Bed Nucleus of the Stria Terminalis in a Stress-Dependent Manner

Abstract

Metabotropic glutamate receptors (mGluRs) are important modulators of excitatory transmission, and have been implicated in anxiety and stress-related behaviors. Previously, we showed that group III mGluR agonists could depress excitatory synaptic transmission in the bed nucleus of the stria terminalis (BNST), an integral component of the anxiety circuitry. Here, we provide converging evidence indicating that this effect is mediated primarily by mGluR8, is exerted presynaptically, and is modulated by noradrenergic signaling and stress. The effects of the group III mGluR agonist L-AP4 on excitatory transmission are not potentiated by the mGluR4-selective allosteric potentiator PHCCC, but are mimicked by the mGluR8-selective agonist DCPG. Consistent with these results, mGluR8-like immunoreactivity is seen in the BNST, and the actions of L-AP4 on excitatory transmission are absent in slices from mGluR8 knockout (KO) mice. Application of DCPG is associated with an increase in paired-pulse evoked glutamate synaptic currents, and a decrease in spontaneous glutamate synaptic current frequency, consistent with a primarily presynaptic action. mGluR8-mediated suppression of excitatory transmission is disrupted ex vivo by activation of a1 adrenergic receptors (a1 ARs). BNST mGluR8 function is also disrupted by both acute and chronic in vivo exposure to restraint stress, and in brain slices from a2A AR KO mice. These studies show that mGluR8 is an important regulator of excitatory transmission in the BNST, and suggest that this receptor is selectively disrupted by noradrenergic signaling and by both acute and chronic stress.

Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent, Norepinephrine-Independent Processes

“…a 1 -AR-Induced Depression of Excitatory Transmission in the dlBNST is Not Blocked by an OX 1 R Antagonist As shown above, orexin A, acting at the OX 1 R, depresses excitatory transmission in the dlBNST. Similarly, previous work in our lab has demonstrated that several other Gq-linked receptors (eg, a 1 -AR, mGluR1, mGluR5) cause a depression of excitatory transmission in the dlBNST (Gosnell et al, 2011;Grueter et al, 2006;McElligott et al, 2010;Winder, 2008, 2009). Although the a 1 -AR antagonist prazosin did not block yohimbine-induced depression of excitatory transmission (see above), to further address possible activation of common downstream effectors, we investigated if an OX 1 R antagonist could block methoxamine (a Gq-linked a 1 -AR)-induced depression in the dlBNST.…”

Targeting metabotropic glutamate receptors for novel treatments of schizophrenia

“…Consistent with this, mGlu 8 KO mice display deficits in hippocampal-dependent learning [219]. Additionally, mGlu 8 suppresses glutamatergic input into the bed nucleus of the stria terminalis (BNST) implicating a role for this receptor in anxiety and stress [220], consistent with results observed in the mGlu 8 KO mice [221]. Similar to both mGlu 4 and mGlu 7 , the neuromodulatory role of mGlu 8 in brain regions implicated in learning and memory suggests that mGlu 8 ligands could be beneficial in treating the cognitive deficits in patients with schizophrenia.…”

Characterization of a Novel Mutation in <b><i>SLC1A1 </i></b>Associated with Schizophrenia

“…Although genetic variations of GRM8 in schizophrenia and the antipsychotic effects of mGluR8 agonists have been inconsistently reported in the literature [71, 72, 73, 74], there are conclusive reports regarding its role in mediating excitatory transmission in response to environmental stressors. In fact, the mGlu8 receptor has been specifically implicated in anxiety and stress-related behaviors and its activation has been shown to produce strong anxiolytic effects [75, 76]. Thus, the observed increase in its expression might represent another adaptive response in SLC1A1 deletion carriers, thereby helping them to deal better with stressful stimuli or events.…”