Nigel S. Bamford

Heterosynaptic Dopamine Neurotransmission Selects Sets of Corticostriatal Terminals

Dopamine input to the striatum is required for voluntary motor movement, behavioral reinforcement, and responses to drugs of abuse. It is speculated that these functions are dependent on either excitatory or inhibitory modulation of corticostriatal synapses onto medium spiny neurons (MSNs). While dopamine modulates MSN excitability, a direct presynaptic effect on the corticostriatal input has not been clearly demonstrated. We combined optical monitoring of synaptic vesicle exocytosis from motor area corticostriatal afferents and electrochemical recordings of striatal dopamine release to directly measure effects of dopamine at the level of individual presynaptic terminals. Dopamine released by either electrical stimulation or amphetamine acted via D2 receptors to inhibit the activity of subsets of corticostriatal terminals. Optical and electrophysiological data suggest that heterosynaptic inhibition was enhanced by higher frequency stimulation and was selective for the least active terminals. Thus, dopamine, by filtering less active inputs, appears to reinforce specific sets of corticostriatal synaptic connections.

Dopamine Modulates Release from Corticostriatal Terminals

Normal striatal function is dependent on the availability of synaptic dopamine to modulate neurotransmission. Within the striatum, excitatory inputs from cortical glutamatergic neurons and modulatory inputs from midbrain dopamine neurons converge onto dendritic spines of medium spiny neurons. In addition to dopamine receptors on medium spiny neurons, D2 receptors are also present on corticostriatal terminals, where they act to dampen striatal excitation. To determine the effect of dopamine depletion on corticostriatal activity, we used the styryl dye FM1-43 in combination with multiphoton confocal microscopy in slice preparations from dopamine-deficient (DD) and reserpine-treated mice. The activity-dependent release of FM1-43 out of corticostriatal terminals allows a measure of kinetics quantified by the halftime decay of fluorescence intensity. In DD, reserpine-treated, and control mice, exposure to the D2-like receptor agonist quinpirole revealed modulation of corticostriatal kinetics with depression of FM1-43 destaining. In DD and reserpine-treated mice, quinpirole decreased destaining to a greater extent, and at a lower dose, consistent with hypersensitive corticostriatal D2 receptors. Compared with controls, slices from DD mice did not react to amphetamine or to cocaine with dopamine-releasing striatal stimulation unless the animals were pretreated with l-3,4-dihydroxyphenylalanine (l-dopa). Electron microscopy and immunogold labeling for glutamate terminals within the striatum demonstrated that the observed differences in kinetics of corticostriatal terminals in DD mice were not attributable to aberrant cytoarchitecture or glutamate density. Microdialysis revealed that basal extracellular striatal glutamate was normal in DD mice. These data indicate that dopamine deficiency results in morphologically normal corticostriatal terminals with hypersensitive D2 receptors.

Age-Dependent Alterations of Corticostriatal Activity in the YAC128 Mouse Model of Huntington Disease

Huntington disease is a genetic neurodegenerative disorder that produces motor, neuropsychiatric, and cognitive deficits and is caused by an abnormal expansion of the CAG tract in the huntingtin (htt) gene. In humans, mutated htt induces a preferential loss of medium spiny neurons in the striatum and, to a lesser extent, a loss of cortical neurons as the disease progresses. The mechanisms causing these degenerative changes remain unclear, but they may involve synaptic dysregulation. We examined the activity of the corticostriatal pathway using a combination of electrophysiological and optical imaging approaches in brain slices and acutely dissociated neurons from the YAC128 mouse model of Huntington disease. The results demonstrated biphasic age-dependent changes in corticostriatal function. At 1 month, before the behavioral phenotype develops, synaptic currents and glutamate release were increased. At 7 and 12 months, after the development of the behavioral phenotype, evoked synaptic currents were reduced. Glutamate release was decreased by 7 months and was markedly reduced by 12 months. These age-dependent alterations in corticostriatal activity were paralleled by a decrease in dopamine D2 receptor modulation of the presynaptic terminal. Together, these findings point to dynamic alterations at the corticostriatal pathway and emphasize that therapies directed toward preventing or alleviating symptoms need to be specifically designed depending on the stage of disease progression.

Repeated Exposure to Methamphetamine Causes Long-Lasting Presynaptic Corticostriatal Depression that Is Renormalized with Drug Readministration

Addiction-associated behaviors such as drug craving and relapse are hypothesized to result from synaptic changes that persist long after withdrawal and are renormalized by drug reinstatement, although such chronic synaptic effects have not been identified. We report that exposure to the dopamine releaser methamphetamine for 10 days elicits a long-lasting (>4 month) depression at corticostriatal terminals that is reversed by methamphetamine readministration. Both methamphetamine-induced chronic presynaptic depression and the drugs selective renormalization in drug-experienced animals are independent of corresponding long-term changes in synaptic dopamine release but are due to alterations in D1 dopamine and cholinergic receptor systems. These mechanisms might provide a synaptic basis that underlies addiction and habit learning and their long-term maintenance.

Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors.

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 GPR88 is robustly expressed in MSNs and is regulated by neuropharmacological drugs, but its contribution to MSN physiology and behavior is unclear. We found that, in the absence of GPR88, MSNs showed increased glutamatergic excitation and reduced GABAergic inhibition, which promoted 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 rescued the molecular and electrophysiological properties and normalized 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.

Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- and D2R-expressing medium spiny neurons is required for amphetamine sensitization

Signaling through N-methyl-d-aspartate–type glutamate receptors (NMDARs) is essential for the development of behavioral sensitization to psychostimulants such as amphetamine (AMPH). However, the cell type and brain region in which NMDAR signaling is required for AMPH sensitization remain unresolved. Here we use selective inactivation of Grin1, the gene encoding the essential NR1 subunit of NMDARs, in dopamine neurons or their medium spiny neuron (MSN) targets, to address this issue. We show that NMDAR signaling in dopamine neurons is not required for behavioral sensitization to AMPH. Conversely, removing NMDARs from MSNs that express the dopamine D1 receptor (D1R) significantly attenuated AMPH sensitization, and conditional, virus-mediated restoration of NR1 in D1R neurons in the nucleus accumbens (NAc) of these animals rescued sensitization. Interestingly, sensitization could also be restored by virus-mediated inactivation of NR1 in all remaining neurons in the NAc of animals lacking NMDARs on D1R neurons, or by removing NMDARs from all MSNs. Taken together, these data indicate that unbalanced loss of NMDAR signaling in D1R MSNs alone prevents AMPH sensitization, whereas a balanced loss of NMDARs from both D1R and dopamine D2 receptor-expressing (D2R) MSNs is permissive for sensitization.

Attenuating GABA A receptor signaling in dopamine neurons selectively enhances reward learning and alters risk preference in mice

Phasic dopamine (DA) transmission encodes the value of reward-predictive stimuli and influences both learning and decision-making. Altered DA signaling is associated with psychiatric conditions characterized by risky choices such as pathological gambling. These observations highlight the importance of understanding how DA neuron activity is modulated. While excitatory drive onto DA neurons is critical for generating phasic DA responses, emerging evidence suggests that inhibitory signaling also modulates these responses. To address the functional importance of inhibitory signaling in DA neurons, we generated mice lacking the β3 subunit of the GABAA receptor specifically in DA neurons (β3-KO mice) and examined their behavior in tasks that assessed appetitive learning, aversive learning, and risk preference. DA neurons in midbrain slices from β3-KO mice exhibited attenuated GABA-evoked IPSCs. Furthermore, electrical stimulation of excitatory afferents to DA neurons elicited more DA release in the nucleus accumbens of β3-KO mice as measured by fast-scan cyclic voltammetry. β3-KO mice were more active than controls when given morphine, which correlated with potential compensatory upregulation of GABAergic tone onto DA neurons. β3-KO mice learned faster in two food-reinforced learning paradigms, but extinguished their learned behavior normally. Enhanced learning was specific for appetitive tasks, as aversive learning was unaffected in β3-KO mice. Finally, we found that β3-KO mice had enhanced risk preference in a probabilistic selection task that required mice to choose between a small certain reward and a larger uncertain reward. Collectively, these findings identify a selective role for GABAA signaling in DA neurons in appetitive learning and decision-making.

Regulation of prefrontal excitatory neurotransmission by dopamine in the nucleus accumbens core

•  Dopamines 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 CB1 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.

Varicella-zoster Virus Retrobulbar Optic Neuritis in a Patient With Human Immunodeficiency Virus

PURPOSE To determine the cause of bilateral retrobulbar optic neuritis followed by progressive outer retinal necrosis in a patient with human immunodeficiency virus (HIV). METHODS Extensive ophthalmologic, neurologic, infectious disease, rheumatologic, and radiologic examinations were performed. RESULTS Cerebrospinal fluid samples taken after the onset of bilateral retrobulbar optic neuritis and before the development of clinical progressive outer retinal necrosis disclosed varicella-zoster virus from polymerase chain reaction and viral culture. CONCLUSION Ophthalmologists and neurologists should consider varicella-zoster virus optic neuritis as a potential precursor of progressive outer retinal necrosis and as a cause of retrobulbar optic neuritis in patients infected with HIV.

Acetylcholine Encodes Long-Lasting Presynaptic Plasticity at Glutamatergic Synapses in the Dorsal Striatum after Repeated Amphetamine Exposure

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 Parkinsons 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 >50 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.