Heterosynaptic GABA_BReceptor Function within Feedforward Microcircuits Gates Glutamatergic Transmission in the Nucleus Accumbens Core

Abstract

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 GABA B heteroreceptor (GABA B R), a G i/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 GABA B R function at glutamatergic synapses within PV-IN-embedded microcircuits in the NAc core of male mice. We found that GABA B R is expressed presynaptically and recruits a noncanonical signaling mechanism to reduce glutamatergic synaptic efficacy at D1(ϩ) and D1(Ϫ) (putative D2) MSN subtypes. Furthermore, PV-INs, a robust source of neuronal GABA in the NAc, heterosynaptically target GABA B R to selectively modulate glutamatergic transmission onto D1(ϩ) MSNs. These findings elucidate a new mechanism of feedforward inhibition and refine mechanisms by which GABA B heteroreceptors modulate mesolimbic circuit function.

Calcium-Permeable AMPA Receptors Promote Endocannabinoid Signaling at Parvalbumin Interneuron Synapses in the Nucleus Accumbens Core

“…To determine if PV-INs [PV(+)-INs] in the NAc core differ from D1(+)- and D1(−)-expressing MSNs in functional CP-AMPAR content, we prepared acute ex vivo brain slices from PV Cre -tdTomato(tdT) f/-STOP-fl (PV tdT ) and D1tdTomato transgenic reporter mice ( Figure 1A ). This strategy allows PV(+) and D1(+) cells in the NAc to be visualized ex vivo , as described previously ( Scudder et al, 2018 ; Manz et al, 2019 ). To confirm that tdT(+) cells in PV tdT mice were PV-INs, we performed current-clamp recordings in tdT(+) cells to determine if tdT(+) cells displayed a fast-spiking electrophysiological profile.…”

An endocannabinoid-regulated basolateral amygdala–nucleus accumbens circuit modulates sociability

“…However, it is possible that inhibition of GABAergic interneurons in the NAc of Shank3B -/animals, by either NpHR-induced reductions in FF inhibition or JZL184 application, was sufficient to restore social function. One possible way that JZL184 could improve SI is via inhibition of glutamatergic BLA synapses and GABAergic fast-spiking interneurons (FSIs) onto MSNs, both of which are regulated by CB1 receptors at the presynaptic level ( Figure 10) (26,65,66). Increases in 2-AG may therefore inhibit activation of NAc FSIs in response to BLA stimulation as well as inhibit GABAergic release from FSIs.…”

Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors

“…Considering that our recent study on the mechanism underlying DBS of the subthalamic nucleus revealed that DBS induces an increase in histamine release in the subthalamic nucleus to alleviate Parkinsonian motor deficits ( 20 ), we speculate that the DBS–NAc core may also induce histamine release in the NAc core to activate the presynaptic H3 receptor, inhibit glutamatergic afferent inputs from the prefrontal cortex, and subsequently ameliorate anxiety- and obsessive-compulsive-like behaviors. Unlike presynaptic GABA ( 48 , 49 ), adenosine ( 48 ), or serotonin ( 50 ) receptors functioning to modulate both excitatory and inhibitory synaptic transmission in NAc, the presynaptic histamine H3 receptor, selectively acting on glutamatergic neurotransmission, may be a better target for the treatment of glutamatergic dysfunction in NAc. Notably, several agonists for the H3 receptor, including RAMH and its prodrugs, have entered clinical trials and proved safe ( 51 , 52 ).…”