α1-Adrenergic Receptor-Induced Heterosynaptic Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted in Mouse Models of Affective Disorders

Abstract

The glutamatergic synapse in specific brain regions has been shown to be a site for convergence of stress and addictive substances. The bed nucleus of the stria terminalis (BNST), a nucleus that relays between higher order processing centers and classical reward and stress pathways, receives dense noradrenergic inputs that are known to influence behavioral paradigms of both anxiety and stress-induced relapse to drug seeking. a 1 -Adrenergic receptors (a 1 -ARs) within this region have been implicated in modulation of the HPA axis and anxiety responses. We found that application of an a 1 -AR agonist produced a long-term depression (LTD) of excitatory transmission in an acute mouse BNST slice preparation. This effect was mimicked by a 20 min, but not a 10 min, application of 100 mM norepinephrine (NE) in a prazosin-sensitive manner. This a 1 -AR LTD was independent of N-methyl-D-aspartate receptor (NMDAR) function unlike previously described a 1 -AR LTD in the hippocampus and visual cortex; however, it was dependent on the activation of L-type voltage gated calcium channels (VGCCs). In addition, a 1 -AR LTD was induced independently of the activation of mGluR5 which can also induce LTD in this region. Furthermore, a 1 -AR LTD was intact in mice receiving an intraperitoneal injection of cocaine but was disrupted in a 2a -AR and NE transporter (NET) knockout (KO) mice. Thus a loss of this plasticity at glutamatergic synapses in BNST could contribute to affective behavioral phenotypes of these mice.

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

“…Previous work has shown that bath application of the a1 AR agonist methoxamine (100 mM) for 20 min induces a1-LTD in the BNST that is modulated by chronic restraint stress (McElligott and Winder, 2008;McElligott et al, 2010). In this study, the same methoxamine application disrupted subsequent mGluR8-induced depression of excitatory transmission in the slice, as did both acute and chronic restraint stress.…”

“…The location of the a1 ARs disrupting mGluR8 function in the BNST is, as yet, unknown. Our lab has shown previously that postsynaptic G-protein signaling is necessary for expression of a1-LTD, suggesting a postsynaptic locus for a1 ARs (McElligott and Winder, 2008). One possibility is that postsynaptic a1 ARs are disrupting presynaptic mGluR8 via a retrograde messenger.…”

“…We have previously reported that the depressive effects of NE on excitatory transmission in the BNST are time dependent (McElligott and Winder, 2008). A 10-min application of NE transiently depresses excitatory transmission in the BNST, whereas a 20-min application induces a1-LTD, which in turn disinhibits the PVN and allows for HPA axis activation (Cecchi et al, 2002).…”

Distinct forms of G q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

“…Previously, we described that mGluR5 activation induces LTD of excitatory transmission in the BNST (13). Additionally, norepinephrine (NE) can induce a time-dependent LTD via the α 1 -AR (19). A particularly interesting feature of α 1 -AR LTD is that it is heterosynaptic in nature in that it does not occur by augmenting NMDA receptor or mGluR5 signaling, although it can be elicited in the same neurons in BNST as mGluR5-LTD (19).…”

“…Additionally, norepinephrine (NE) can induce a time-dependent LTD via the α 1 -AR (19). A particularly interesting feature of α 1 -AR LTD is that it is heterosynaptic in nature in that it does not occur by augmenting NMDA receptor or mGluR5 signaling, although it can be elicited in the same neurons in BNST as mGluR5-LTD (19). Based on this interaction and the studies in hippocampus (17) and visual cortex (18), we hypothesized that α 1 -AR LTD and mGluR5 LTD share common mechanisms and are recruited by similar environmental stimuli.…”