Group II and III Metabotropic Glutamate Receptors Suppress Excitatory Synaptic Transmission in the Dorsolateral Bed Nucleus of the Stria Terminalis

Abstract

Conditions such as anxiety, drug abuse, and post-traumatic stress disorder are thought to reflect alterations in central nervous system stress and reward circuitry. Recent evidence suggests a key component of this circuitry is the bed nucleus of the stria terminalis (BNST). In particular, regulation of glutamatergic transmission in the BNST plays a critical role in animal performance on anxiety tasks. Metabotropic glutamate receptors (mGluRs) have been implicated in stress and drug addiction and are known to regulate glutamatergic transmission in many brain regions. We have utilized both extracellular field potential and whole-cell patch-clamp recording in an in vitro slice preparation of mouse dorsal anterolateral BNST to determine whether G i/o -linked mGluRs modulate excitatory transmission in this region. We find that activation of group II and group III mGluRs in an in vitro slice preparation of the dBNST causes a depression of excitatory transmission. The depression evoked by group II mGluR activation may represent a form of synaptic plasticity as prolonged activation of the receptor produces a long-term depression of glutamatergic transmission. Based on paired-pulse ratio analysis, initiation of depression by group II and group III mGluR subfamilies appears to, at least in part, involve decreased glutamate release. In total, our data suggest a plausible site of action for some of the anxiolytic effects of group II and group III mGluR agonists.

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

“…To more directly test whether mGluR8 activation has effects on excitatory transmission in the BNST, we utilized the mGluR8 modulates excitatory transmission in the BNST HB Gosnell et al mGluR8-selective agonist DCPG, which has also been previously shown to depress excitatory transmission in this region (Grueter and Winder, 2005). Consistent with this, we found that a 20-min application of DCPG depressed excitatory transmission in the BNST as examined by field potential recordings (Figure 2a).…”

“…In contrast to ionotropic glutamate receptors, the slower nature of mGluR signaling allows for potentially more long-lasting, adaptive changes in synaptic strength. Within the BNST, agonists to group I-III mGluRs depress glutamatergic transmission (Muly et al, 2007;Grueter and Winder, 2005;Grueter et al, 2006). Consistent percent depression by methoxamine is modestly but significantly attenuated in naive vs acutely restrained mice (stress: 18.0 ± 1.7 peak average percent depression vs 24.4 ± 3.0 for naive controls; po0.05, Student's t-test, n ¼ 4 to 5).…”

“…We have previously reported that the group III mGluR agonist L-AP4 depresses excitatory transmission in the BNST (Grueter and Winder, 2005). Here, we used field potential recordings and local afferent stimulation in the anterolateral dBNST to further probe the specific group III mGluR subtypes involved in mediating the effects of L-AP4 in the dBNST ( Figure 1a).…”

“…In the BNST, the group III mGluR agonist L-AP4 and the mGluR8-selective agonist DCPG have depressive effects on excitatory transmission, suggesting expression of mGluR8 and potentially other group III mGluRs in this region (Grueter and Winder, 2005). With activity in the BNST being critical during stress exposure, presynaptic mGluRs are well positioned to regulate excitatory inputs coming into this region.…”

Mechanisms of fear extinction

“…Within the amygdala, mGluR7 is localized to presynaptic terminals of glutamatergic neurons 179 and may act to inhibit glutamate release. 180 Callaerts-Vegh et al 181 compared mGluR7À/À mice with mGluR7 þ / þ littermate controls on a variety of tasks, including a conditioned emotional response (CER) procedure in which tone-shock pairings were introduced while the animals performed a previously trained nose-poke task in which nose pokes were reinforced by delivery of food pellets. Both groups of animals learned to nose poke equally well and both came to suppress nose poking during tone presentations equally quickly.…”