TY - JOUR T1 - Heterosynaptic GABA<sub>B</sub> receptor function within feedforward microcircuits gates glutamatergic transmission in the nucleus accumbens core JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.1395-19.2019 SP - 1395-19 AU - Kevin M. Manz AU - Andrew G. Baxley AU - Zack Zurawski AU - Heidi E. Hamm AU - Brad A. Grueter Y1 - 2019/10/02 UR - http://www.jneurosci.org/content/early/2019/10/02/JNEUROSCI.1395-19.2019.abstract N2 - Complex circuit interactions within the nucleus accumbens (NAc) facilitate goal-directed behavior. Medium spiny neurons (MSNs) mediate NAc output by projecting to functionally divergent brain regions, a property conferred, in part, by the differential projection patterns of D1- and D2 dopamine receptor-expressing MSNs. Glutamatergic afferents to the NAc direct MSN output by recruiting feedforward inhibitory microcircuits comprised of parvalbumin (PV)-expressing interneurons (INs). Furthermore, the GABAB heteroreceptor (GABABR), a Gi/o-coupled G protein-coupled receptor, is expressed at glutamatergic synapses throughout the mesolimbic network, yet its physiological context and synaptic mechanism within the NAc remains unknown. Here, we explored GABABR function at glutamatergic synapses within PV-IN-embedded microcircuits in the NAc core of male mice. We found that GABABR is expressed presynaptically and recruits a non-canonical signaling mechanism to reduce glutamatergic synaptic efficacy at D1(+) and D1(-) [putative D2] MSN subtypes. Furthermore, PV-INs, a robust source of neuronal GABA in the NAc, heterosynaptically target GABABR to selectively modulate glutamatergic transmission onto D1(+) MSNs. These findings elucidate a new mechanism of feedforward inhibition and refine mechanisms by which GABAB heteroreceptors modulate mesolimbic circuit function.SIGNIFICANCE STATEMENTGlutamatergic transmission in the nucleus accumbens (NAc) critically contributes to goal-directed behaviors. However, intrinsic microcircuit mechanisms governing the integration of these synapses remain largely unknown. Here, we show that parvalbumin-expressing interneurons within feedforward microcircuits heterosynaptically target GABAB heteroreceptors (GABABR) on glutamate terminals. Activation of presynaptically-expressed GABABR decreases glutamatergic synaptic strength by engaging a non-canonical signaling pathway that interferes with vesicular exocytotic release machinery. These findings offer mechanistic insight into the role of GABAB heteroreceptors within reward circuitry, elucidate a novel arm to feedforward inhibitory networks, and inform the growing use of GABABR-selective pharmacotherapy for various motivational disorders, including addiction, major depressive disorder, and autism (Cousins, Roberts, &amp; Wit, 2002; Jacobson, Vlachou, Slattery, Li, &amp; Cryan, 2018; Kahn et al., 2009; Pisansky et al., 2019; Stoppel et al., 2018). ER -