Nigel S. Bamford, MD, FANA

The striatum is a cluster of cells within the brain that helps execute normal movements and establishes goal directed behaviors. The symptoms of Parkinsonism and other debilitating neuropsychiatric disorders in children are caused by abnormal dopamine and acetylcholine availability in the striatum. Dr. Bamford’s laboratory investigations show how dopamine can trigger lasting changes in acetylcholine and will generate new pharmacological targets and treatments for parkinsonism and the dyskinetic motor movements that accompany treatment.

Dr. Bamford has a strong track record of research funding, ranging from private grants to NIH. Dr. Bamford’s laboratory investigations focus on the function of the mammalian corticostriatal system. This system includes a collection of neurons that connect the cerebral cortex and striatum. The striatum plays an essential role in cognition, motor control, cue-dependent behaviors and abnormal function underlies aspects of numerous developmental, neurological, and psychiatric disorders, including Tourette syndrome, attention deficit–hyperactivity disorder, substance abuse, Parkinson’s disease, and Huntington’s disease. New treatments are needed and Bamford’s investigations offer critical insights into novel treatment options. In these disorders, too much or too little dopamine alters striatal excitation, resulting in clinical symptoms. To gain insight into synaptic plasticity induced by alterations in dopamine availability, the Bamford Lab combines behavioral investigations with optical, electrophysiological, biochemical, and immunohistochemical methods to determine the mechanisms underlying striatal modulation of glutamate release by dopamine, GABA, endocannabinoids, adenosine, and acetylcholine.

Since establishing his laboratory at the University of Washington in 2002, Dr. Bamford has published exceptional papers in Neuron, the Journal of Neuroscience, the Journal of Physiology, Annals of Neurology, and Nature Neuroscience. His work utilizes a novel technique, developed by Bamford and David Sulzer at Columbia University, which allows direct optical visualization of presynaptic cortical terminals in the striatum. This technique provides a robust way to measure kinetics of glutamate release from individual synaptic terminals. Investigations demonstrate that glutamate release from cortical projections in the motor striatum is directly regulated by dopamine, adenosine, and endocannabinoids. By regulating a subset of terminals, dopamine and these other neuromodulators alter the parallel processing of cortical inputs to the striatum, affecting striatal filtering of cortical information that leads to specific behaviors in mice (Neuron, 2004). 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 (Journal of Neuroscience, 2004).

Dopamine excess, as modeled by repeated use of the psychostimulants amphetamine and methamphetamine, produces a chronic striatal depression that is renormalized by drug reinstatement. This effect is dose dependent, long lasting (>140 days) 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 suppressed terminals correlates with locomotor sensitization and the model extends to drug intake escalation, both hallmarks of addiction (Neuron, 2008). These findings received wide press coverage and included reports on BBC National and World Radio, ABC, Washington Post, Science and Nature, New Scientist, and Scientific American.

In other studies, Bamford and co-workers 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 (Journal of Neuroscience, 2008).

More recently, the Bamford lab showed how dopamine, endocannabinoids, and adenosine modulate frontal cortical projections to the nucleus accumbens (Journal of Physiology, 2012). In this study, workers combined optical recordings of presynaptic release with whole-cell electrophysiology in CB₁ receptor-null mice and bacterial artificial chromosome (BAC) transgenic mice

Bamford also published a important article describing the behavioral effects of prenatal cocaine exposure (PCE) and the synaptic and biochemical mechanisms that might account for those behaviors (Annals of Neurology, 2013). 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, Bamford and co-workers used a murine model for PCE to characterize abnormal dopamine-dependent behaviors and synaptic plasticity of the corticostriatal pathway. They 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 GABA_A 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 approaches for behaviors that follow PCE.

The Bamford laboratory has collaborated extensively with the Palmiter laboratory at the University of Washington on a number of projects. We showed that amphetamine sensitization requires balanced NMDA receptor activity in dopamine D1 and D2 receptor-expressing medium spiny neurons (PNAS, 2011) and that attenuating GABA_A receptor signaling in dopamine neurons selectively enhances reward learning and alters risk preference in mice (Journal of Neuroscience, 2011). In another paper published in Nature Neuroscience (2012), we showed that the orphan G-protein-coupled receptor 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 medium spiny neurons activation in the absence of GPR88 underlies behavioral deficits and its dysfunction may contribute to behaviors observed in neuropsychiatric disease.

Dr. Bamford’s study published in the Journal of Neuroscience (2013) shows how acetylcholine encodes long-lasting presynaptic plasticity at glutamatergic synapses in the dorsal striatum after repeated amphetamine. Locomotion and cue-dependent behaviors are modified through corticostriatal signaling, where 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. He showed 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 more than 50 days 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 correlated with locomotor responses following a drug challenge, suggesting that it may underlie the sensitization process. Experiments in slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons (TANs) contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Thus, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by TANs and returns to normal upon re-exposure 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.

The Bamford laboratory is currently supported by the NIH: Dopamine-Induced Striatal Synaptic Plasticity (2R01NS060803-07).