The striatum regulates motor control, reward, and learning. Abnormal function of striatal GABAergic medium spiny neurons (MSNs) is believed to contribute to the deficits in these processes that are observed in many neuropsychiatric diseases. The orphan G-protein-coupled receptor (GPCR) GPR88 is robustly expressed in MSNs and regulated by neuropharmacological drugs, but its contribution to MSN physiology and behavior is unclear. Here we show that in the absence of GPR88, MSNs have increased glutamatergic excitation and reduced GABAergic inhibition that together promote enhanced firing rates in vivo, resulting in hyperactivity, poor motor-coordination, and impaired cue-based learning in mice. Targeted viral expression of GPR88 in MSNs rescues the molecular and electrophysiological properties and normalizes behavior, suggesting that aberrant MSN activation in the absence of GPR88 underlies behavioral deficits and its dysfunction may contribute to behaviors observed in neuropsychiatric disease.

Key points• Dopamine's control over excitatory signals from the cortex to the nucleus accumbens is thought to underlie motor learning, behavioural reinforcement and drug dependence.• In this study, we combined optical recordings of presynaptic release with whole-cell electrophysiology in CB 1 receptor-null mice and bacterial artificial chromosome (BAC) transgenic mice with fluorescently labelled D1 and D2 receptor-expressing neurons to identify the specific interactions between dopamine and glutamate signalling at individual cortical terminals within the nucleus accumbens core.• Experiments showed that dopamine produces frequency-dependent filtering of low-probability release synapses. At low frequencies, D1 receptors excited striatal output neurons of the striatonigral and striatopallidal pathways, while D2 receptors specifically inhibited neurons of the striatopallidal pathway. At higher frequencies, the dopamine-dependent release of adenosine and endocannabinoids promoted further temporal filtering of cortical signals entering both output pathways.• These results help us understand how dopamine provides frequency and temporal filtering of cortical information by promoting activity through the striatonigral pathway, while inhibiting weak signals.Abstract Interactions between dopamine and glutamate signalling within the nucleus accumbens core are required for behavioural reinforcement and habit formation. Dopamine modulates excitatory glutamatergic signals from the prefrontal cortex, but the precise mechanism has not been identified. We combined optical and electrophysiology recordings in murine slice preparations from CB 1 receptor-null mice and green fluorescent protein hemizygotic bacterial artificial chromosome transgenic mice to show how dopamine regulates glutamatergic synapses specific to the striatonigral and striatopallidal basal ganglia pathways. At low cortical frequencies, dopamine D1 receptors promote glutamate release to both D1 and D2 receptor-expressing medium spiny neurons while D2 receptors specifically inhibit excitatory inputs to D2 receptor-expressing cells by decreasing exocytosis from cortical terminals with a low probability of release. At higher cortical stimulation frequencies, this dopaminergic modulation of presynaptic activity is occluded by adenosine and endocannabinoids. Glutamatergic inputs to both D1 and D2 receptor-bearing medium spiny neurons are inhibited by adenosine, released upon activation of NMDA and AMPA receptors and adenylyl cyclase in D1 receptor-expressing cells. Excitatory inputs to D2 receptor-expressing cells are specifically inhibited by endocannabinoids, whose release is dependent on D2 and group 1 metabotropic glutamate receptors. The convergence of excitatory and inhibitory modulation of corticoaccumbal activity by dopamine, adenosine and endocannabinoids creates subsets of corticoaccumbal inputs, selectively and temporally reinforces strong cortical signals through the striatonigral pathway while inhibiting the weak, and may provide a mechanism whereby conti...

Locomotion and cue-dependent behaviors are modified through corticostriatal signaling whereby short-term increases in dopamine availability can provoke persistent changes in glutamate release that contribute to neuropsychiatric disorders, including Parkinson's disease and drug dependence. We found that withdrawal of mice from repeated amphetamine treatment caused a chronic presynaptic depression (CPD) in glutamate release that was most pronounced in corticostriatal terminals with a low probability of release and lasted Ͼ50 d in treated mice. An amphetamine challenge reversed CPD via a dopamine D1-receptor-dependent paradoxical presynaptic potentiation (PPP) that increased corticostriatal activity in direct pathway medium spiny neurons. This PPP was correlated with locomotor responses after a drug challenge, suggesting that it may underlie the sensitization process. Experiments in brain slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Therefore, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by tonically active interneurons and returns to normal upon reexposure to amphetamine, suggesting that this paradoxical return of striatal activity to a more stable, normalized state may represent an additional source of drug motivation during abstinence. IntroductionThe neocortex refines volitional movements and goal-directed behaviors through the corticostriatal-basal ganglia-thalamocortical feedback loop (Albin et al., 1989;Jog et al., 1999). The input of this neural network consists of glutamatergic cortical afferents that excite D1-class (D1R) and D2-class dopamine receptor (D2R)-expressing striatal medium-sized spiny neurons (MSNs), which form distinct direct and indirect pathways that promote and suppress competing motor movements, respectively (Pennartz et al., 1994; Nicola et al., 2000). Modulation of these excitatory corticostriatal synapses is determined by the availability of dopamine and acetylcholine, which are necessary for the establishment of reward, attention, and motor learning (Kalivas and Volkow, 2005;Cepeda et al., 2010). Emerging evidence suggests that abnormalities in the availability of these neuromodulators may promote an imbalance between direct and indirect striatal pathways (Beutler et al., 2011;Kozorovitskiy et al., 2012; to produce the motor and neuropsychological symptoms of Parkinsonism and drug dependence Bamford and Cepeda, 2009).Addiction is considered a chronic, allostatic condition (Ahmed and Koob, 2005) characterized by drug seeking behaviors and relapse after withdrawal (Kalivas and Volkow, 2005). Psychostimulants have a high potential for abuse because they acutely increase brain dopamine levels (Sulzer, 2011) and their repeated use can trigger long-lasting changes in striatal glutamate (Pierce et al., 1996; Cornish et al., 1999; and acetylcholine (Abercrombie and DeBoer, 1997;Bamford...

Objective-Prenatal cocaine exposure (PCE) can cause persistent neuropsychological and motor abnormalities in affected children, but the physiological consequences of PCE remain unclear. Conclusions drawn from clinical studies can sometimes be confounded by poly-substance abuse and nutritional deprivation. However, existing observations suggest that cocaine exposure in utero, as in adults, increases synaptic dopamine and promotes enduring dopamine-dependent plasticity at striatal synapses, altering behaviors and basal ganglia function.Methods-We used a combination of behavioral measures, electrophysiology, optical imaging, and biochemical and electrochemical recordings to examine corticostriatal activity in adolescent mice exposed to cocaine in utero.Results-We show that PCE caused abnormal dopamine-dependent behaviors, including heightened excitation following stress and blunted locomotor augmentation to repeated treatment with amphetamine. These abnormal behaviors were consistent with abnormal GABA interneuron function, which promoted a reversible depression in corticostriatal activity. PCE hyperpolarized and reduced tonic GABA currents in both fast-spiking and PLTS-type GABA interneurons to increase tonic inhibition at GABA B receptors on presynaptic corticostriatal terminals. While D2 receptors paradoxically increased glutamate release following PCE, normal corticostriatal modulation by dopamine was reestablished with a GABA A R antagonist.Interpretation-The dynamic alterations at corticostriatal synapses that occur in response to PCE parallel the reported effects of repeated psychostimulants in mature animals, but differ in being specifically generated through GABA. Our results indicate that approaches which normalize GABA and D2 receptor-dependent synaptic plasticity may be useful for treating the behavioral effects of PCE and other developmental disorders that are generated through abnormal GABAergic signaling.

Synaptic incorporation of NMDARs is regulated by GluN2 subunits with different rules controlling GluN2A- and GluN2B-containing receptors; while GluN2B containing receptors are constitutively incorporated into synapses, GluN2A incorporation is activity-dependent. We expressed electrophysiologically tagged NMDARs in rat hippocampal slices in order to identify the molecular determinants controlling the mode of synaptic incorporation of NMDARs. Expressing chimeric GluN2 subunits, we identified a putative N-glycosylation site present in GluN2B, but not on GluN2A, as necessary and sufficient to drive NMDARs into synapses in an activity-independent manner. This suggests a novel mechanism for regulating activity driven changes and trafficking of NMDARs to the synapse.