Behavioral Role of GluN2D-Containing NMDA Receptors in BNST
Gregory J. Salimando, Minsuk Hyun, Kristen M. Boyt, and Danny G. Winder
(see pages 3949–3968)
NMDA receptors (NMDARs) are essential contributors to synaptic communication and plasticity throughout the nervous system. It is not surprising, therefore, that disruption of NMDAR function is associated with numerous developmental, neurological, and psychiatric conditions, including intellectual disability, schizophrenia, autism, and depression. Unfortunately, however, the ubiquitous expression of NMDARs makes them problematic targets for treating these conditions. For example, the nonspecific NMDAR channel blocker ketamine is remarkably effective in relieving depression, but it also induces psychosis, limiting its usefulness as an antidepressant. Such problems might be circumvented by targeting specific subsets of NMDARs. Indeed, whereas systemic ketamine relieves depression, knocking out NMDARs containing GluN2D subunits increases depression-like behavior in mice (Yamamoto et al., 2017, Neuropharmacology 112:188). Because NMDAR composition varies across brain regions, cell types, and developmental periods, identifying NMDAR subtypes and brain regions that contribute to unwanted conditions might enable the development of targeted therapies.
With this goal in mind, Salimando et al. asked how loss of GluN2D affected activity and plasticity in the bed nucleus of the stria terminalis (BNST), a part of the extended amygdala. They chose this area because they found that constitutive Glun2D knockout increased anxiety-related as well as depression-related behaviors, and because the BNST is thought to promote anxiety-related behaviors, especially in response to stress. Notably, although Grin2d mRNA, which encodes GluN2D, was present on a relatively small proportion of BNST neurons, it was present in most cells that expressed corticotropin-releasing factor (CRF), a peptide involved in stress responses. Furthermore, the frequency and amplitude of spontaneous EPSCs and the amplitude of miniature EPSCs were greater in CRF-expressing BNST neurons in GluN2D-deficient mice than in controls, while the amplitude of spontaneous IPSCs and the paired-pulse ratio were lower. Consequently, CRF-expressing BNST neurons in GluN2D-deficient mice were more active than those of controls in vivo. Short-term plasticity was also impaired in GluN2D-deficient mice.
These results suggest that abnormal activity in BNST CRF neurons contributes to anxiety-related and depression-related behaviors in GluN2D-deficient mice. Surprisingly, however, knocking out GluN2D selectively in BNST of mature mice increased depression-like behaviors without altering anxiety-like behaviors. Therefore, anxiety-like behaviors likely result from loss of GluN2D during development or in other brain regions.
A retrograde tracer (magenta) injected into the basal amygdala labels a small number of neurons in the VTA. See Tang et al. for details.
Role for Dopamine Projections to Amygdala in Fear Learning
Wei Tang, Olexiy Kochubey, Michael Kintscher, and Ralf Schneggenburger
(see pages 3969–3980)
The amygdala is a key region for generating behavioral and physiological responses to threats. Information about noxious and innocuous sensory stimuli converges in the lateral nucleus of the amygdala. Although innocuous stimuli usually elicit weak responses, after they are repeated paired with noxious stimuli, they begin to evoke spiking in neurons that project to the basal nucleus (BA). BA neurons also acquire responses to conditioned stimuli, and they activate neurons in the central nucleus (CeA) that elicit defensive responses through projections to the brainstem and other regions. Thus, plasticity in amygdala circuits underlies fear learning. This plasticity does not occur in isolation, however. For example, the hippocampus and prefrontal cortex also contribute to fear learning. Some evidence suggests that dopaminergic projections from the ventral tegmental area (VTA) to the amygdala contribute to fear learning as well, but whether these particular neurons are activated by aversive stimuli and whether the amygdala neurons they target mediate fear learning or other functions has been unclear.
Tang et al. provide strong evidence that dopaminergic projections from VTA to BA are involved in fear conditioning in mice. Many axons of VTA neurons that express the dopamine transporter (DAT) were present in the amygdala, particularly in the CeA and BA. Retrograde labeling confirmed that some VTA neurons—albeit a relatively small population—projected to BA. Furthermore, some DAT-expressing VTA neurons responded to noxious shock stimuli, and many of these neurons acquired responses to conditioned auditory stimuli during fear conditioning. Labeling with c-fos confirmed that tone–shock pairing increased the activation of DAT-expressing VTA neurons that projected to BA. Finally, silencing dopaminergic VTA neurons or their axons in the BA during footshock delivery reduced subsequent freezing responses to the paired conditioned stimulus.
These results suggest that a relatively small population of dopaminergic VTA neurons project to the BA and enhance fear learning. Given that the VTA neurons acquired responses to conditioned stimuli, future work should investigate whether they are necessary for formation of fear associations, retrieval of these associations, or both. Which receptors and BA cell types dopamine acts on, and how this activity promotes responses to conditioned stimuli, must also be determined.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.
