Nigel S. Bamford, MD

Dr. Bamford's basic science research focuses on function and regulation of striatal synaptic activity in the mammalian basal ganglia. The neostriatum plays an important role in cognition, voluntary movement and addiction. As such, evaluation of striatal function is paramount to understanding numerous developmental, neurological, and psychiatric disorders, including Tourette syndrome, attention deficit hyperactivity disorder, substance abuse, Parkinsons disease and Huntingtons disease. New treatments are needed and Bamfords investigations offer critical insights into novel treatment options.

Current laboratory investigations focus on the function of the mammalian corticostriatal system (the collection of neurons that connect the cerebral cortex and striatum) and its role in motor learning as well as the mechanisms underlying substance abuse, Parkinsons disease and Huntingtons disease. In these disorders, too much or too little dopamine is thought to alter striatal excitation, resulting in clinical symptoms. To gain insights into synaptic plasticity induced by alterations in dopamine availability, the Bamford Lab combine behavioral investigations with optical, electrophysiological, and immunohistochemical methods to observe the effects of dopamine and acetylcholine on glutamate release in the striatum. Bamford has published many high quality papers in Neuron, the Journal of Neuroscience, Annals of Neurology, and Nature Neuroscience. His work describes a newly developed technique that allows direct visualization and measurement of release from presynaptic cortical terminals within the striatum. These investigations demonstrate that glutamate release from cortical projections in the motor striatum is directly regulated by dopamine through D2 receptors located on corticostriatal terminals. By regulating a subset of terminals, dopamine release alters the parallel processing of cortical inputs to the striatum, affecting striatal excitation. Using dopamine-deficient mice and dopamine depleted mice, Bamford demonstrated that dopamine is not required during development for functional dopamine receptors. Dopamine depletion results in hypersensitive dopamine receptors that result in aberrant striatal function resulting in motor dyskinesias. Dopamine excess, as modeled by repeated use of amphetamine and methamphetamine, produces a chronic striatal depression that is renormalized by drug reinstatement. This effect is dose dependent, long lasting and is dependent on a new D1 receptor effect seen only in animals with previous psychostimulant experience. During withdrawal, a psychostimulant challenge produces a paradoxical increase in glutamate release. This increase in glutamate from depressed terminals appears to determine locomotor sensitization and the model extends to drug intake escalation both hallmarks of addiction. These findings received world-wide press coverage and included reports on BBC National and World Radio, ABC, Washington Post, Science and Nature, New Scientist, and Scientific American. Dr. Bamford also found that the huntingtin mutation produces age-dependent alterations in corticostriatal activity that is paralleled by a decrease in dopamine D2 receptor modulation of the presynaptic terminal. Taken together, these findings point to dynamic alterations in the corticostriatal pathway and emphasize that therapies directed toward alleviating or preventing symptoms need to be specifically designed depending on the progression of the disorder. This year, the Bamford lab showed how dopamine, endocannabinoids, and adenosine modulate frontal cortical projections to the nucleus accumbens (Wang et. Al., Journal of Physiology, 2012). 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 to identify the specific interactions between dopamine and glutamate signaling at individual cortical terminals within the nucleus accumbens core. The work showed that 1) dopamine enhances cortical input to both D1- and D2 receptor-expressing medium spiny neurons (MSNs) in the nucleus accumbens core via presynaptic D1 receptors, suggesting a functional difference between dopamine-glutamate interactions in the ventral and dorsal striatum. 2) Dopamine specifically inhibits glutamate input to D2 receptor-expressing medium spiny neurons (MSNs) via D2 receptors in the absence of cortical activity and endocannabinoid signaling. 3) Dopamine indirectly inhibits presynaptic activity of both D1- and D2 receptor-expressing MSNs through adenosine, while endocannabinoids specifically-promote temporal- and activity-dependent filtering of cortical inputs to D2 receptor-bearing cells. 4) The direct excitatory actions by D1 receptors are occluded by striatal activation, which encourages adenosine release and corticoaccumbal inhibition. 5) The direct inhibitory actions by D2 receptors are occluded by striatal activation, which encourages endocannabinoid release and a broader inhibition of excitatory inputs. 6) Presynaptic inhibition by adenosine is dependent on AMPA and NMDA receptor activation as well as adenylate cyclase in D1R-bearing MSNs. Thus, the 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 pathway, 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. Dr. Bamford also published a seminal article describing the behavioral effects of prenatal cocaine exposure (PCE) and the synaptic and biochemical mechanisms that might account for those behaviors. PCE remains a serious health problem and can produce significant developmental and motor disabilities in affected humans. Observations in the clinic and laboratory strongly suggest that PCE causes corticostriatal dysfunction, but this important pathway has never been investigated. In this manuscript, we used a murine model for PCE to characterize abnormal dopamine-dependent behaviors and synaptic plasticity of the corticostriatal pathway. Behavioral measures were combined with electrophysiology, optical imaging, biochemical and electrochemical recordings to identify the interactions between glutamate, GABA and dopamine signaling at individual cortical terminals within the motor striatum. We found that PCE reduces body growth and modifies dopamine-dependent motor behaviors in adolescent mice. Abnormal motor-learning and blunted locomotor responses to repeated amphetamine were paralleled by a reversible GABA-dependent over-inhibition at corticostriatal synapses and a reduction in phasic dopamine release capacity. The release of dopamine promoted normal corticostriatal filtering in controls, but alleviated GABA-mediated inhibition and paradoxically increased corticostriatal activity in those mice with a history of PCE. While GABAA receptors had no effect on presynaptic corticostriatal activity in controls, their inhibition normalized synaptic function following PCE and prevented D2 receptor-dependent paradoxical presynaptic potentiation suggesting new therapeutic avenues. In collaboration with the Palmiter laboratory, we showed that amphetamine sensitization requires balanced NMDA receptor activity in dopamine D1 and D2 receptor-expressing medium spiny neurons (Beutler et. al., PNAS, 2011) and that attenuating GABAA receptor signaling in dopamine neurons selectively enhances reward learning and alters risk preference in mice (Parker et. Al., J Neuroscience, 2011). In another paper published in Nature Neuroscience, we showed that the orphan G-protein-coupled receptor (GPCR) GPR88 is robustly expressed in medium spiny neurons in the striatum and regulated by neuro-pharmacological drugs. In the absence of GPR88, medium spiny neurons 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 medium spiny neurons 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 (Quintana et. al., Nature Neuroscience, 2012). Further information can be obtained on the Bamford laboratory website http://depts.washington.edu/nigellab/index.html