Canadian College of Neuropsychopharmacology - Young Investigator Award Winner Biography

Biography

The 2010 Young Investigator Award will be presented to Dr. Jean Martin Beaulieu and Dr. Cecilia Flores at the 33rd Annual Meeting of the Canadian College of Neuropsychopharmacology in Ottawa, Ontario,. The Young Investigator Award, sponsored by AstraZeneca Canada, is designed to recognize outstanding contributions in the field of research in neuropsychopharmacology by a young basic or clinical investigator in Canada.

Dr. Jean Martin Beaulieu

Dr. Beaulieu has received outstanding research training, initially doing Ph.D. studies in the laboratory of Dr. Jean-Pierre Julien at McGill from 1995-2001 on the interactions of peripherin and neurofilament and roles in neurodegenerative disease, and then doing post-doctoral studies in the laboratory of Dr. Marc Caron at Duke University from 2001-7. He is currently Assistant Professor, Department of Anatomy and Physiology, Université Laval, and Canadian Research Chair (Tier II) in Molecular Psychiatry. He has already been very successful in securing prestigious external funding including grants from Canada Foundation for Infrastructure, Human Frontier Science Program, and NSERC. Within the last 5 years he has published 16 papers in outstanding journals (Neuron, PNAS, Cell, JBC, etc.), which have been extensively cited (>100 citations) and highlighted (e.g., Science STKE, Faculty of 1000) because of the fundamental importance of the findings.

Importantly, working in Dr. Caron's lab Dr. Beaulieu has developed a novel approach of "in vivo signal transduction" analysis, by using knockout mouse models and subjecting them to a combination of biochemical, behavioral and pharmacological analysis. In these experiments Dr. Beaulieu has not only revealed novel dopamine signaling pathways, but has directly assessed their importance in behavioral alterations that may mimic aspects of mental illness, and their role in response to therapeutic compounds such as lithium, which is used to treat bipolar disorder. In so doing, he has uncovered novel signaling pathways that are implicated in mental illness and can be targeted by new, more highly-specific classes of therapeutic compounds. These findings have immense potential to lead to a new understanding of mental illness in man and to develop new treatments for these disorders.

Dr. Beaulieu's major research contribution (Beaulieu et al., 2005 Cell 122: 261) has been the identification of a new signaling cascade through which dopamine D2 receptors regulate the kinases Akt and glycogen synthase kinase-3 (GSK3) and the demonstration of the importance of this pathway in the regulation of behavior by dopamine ((Beaulieu et al., 2004 PNAS 101: 5099; 2007 J. Neurosci 27: 881). Briefly, stimulation of the D2 receptor (D2R) in the mouse striatum results in Akt inactivation and concomitant activation of GSK3?. Importantly, the regulation of Akt and GSK3 by dopamine depends on the multifunctional protein scaffold beta-arrestin 2 (?Arr2) and is independent from canonical G protein regulated second messenger systems ((Beaulieu et al., 2004 PNAS 101: 5099; 2005 Cell 122: 261). Activation of this D2 receptors by tonic DA and/or dopaminergic drugs leads to the formation of a signaling complex composed of Akt, ?Arr2, and the protein phosphatase 2A (PP2A), which dephosphorylates/inactivates Akt, as demonstrated pharmacologically (Beaulieu et al., 2005). Furthermore, regulation of Akt/GSK3 signaling by ?Arr2 plays an important role for the expression of behavioral responses to drugs on dopamine neurotransmission (Beaulieu et al., 2005 Cell 122: 261) and has provided a new molecular mechanism of action for lithium (Beaulieu et al., 2008 Cell 132: 125). The identification by Dr. Beaulieu of this new cell signaling mechanism of the dopamine D2 receptor has had a huge impact and was highlight as "Breakthrough of the Year" by Science STKE, a premier signaling review Web site.

As mentioned above, in his studies Dr. Beaulieu has also uncovered a new mechanism of action for lithium. Over the years, lithium has been shown to inhibit inositol monophosphatases (IMPAs), GSK3 and other targets, but the mechanism by which it regulates behavior has remained unclear. Dr Beaulieu's work has identified a new mechanism by which lithium regulates both GSK3 activity and behavior. His work has shown that the Akt-?Arr2-PP2A protein complex is a new and direct target of lithium. Absence of ?Arr2 prevented the regulation of Akt and GSK3 signaling by lithium. Furthermore ?Arr2 knockout mice lack behavioral responsiveness to lithium following both acute and chronic lithium administration (Beaulieu et al., 2008 Cell 132: 125). These results are a very important consequence of the identification of a new signaling cascade by Dr Beaulieu and may lead to the development of new therapeutic approaches for bipolar disorders and other psychiatric conditions for which lithium is used.

Arrestin-mediated signaling may also be relevant antipsychotic action. Interestingly a recent study of antipsychotic action on arrestin recruitment and G protein mediated signaling suggests that these drugs share a common molecular mechanism involving inhibition of D2(L)R/ ?Arr2-mediated signaling (Masri et al., 2008 PNAS 105, 13656). Thus, the identification by Dr. Beaulieu of the Akt-?Arr2-PP2A protein complex as a downstream effector of D2 receptor signaling has paved the way for the development of new drugs having biased agonist or antagonist properties for these D2 receptor signaling components.

New signal integrator for dopamine and 5-HT receptor signaling. In addition to its regulation by dopamine, GSK3 is also responsive to several drugs acting on 5-HT neurotransmission. Tph2 is the rate-limiting enzyme for serotonin synthesis in neurons and mutations in this gene can directly affect serotonin production in the brain. Using Tph2 mutant mice displaying an 80% reduction in brain serotonin synthesis, Dr Beaulieu demonstrated that regulation of GSK3 by 5-HT is important for the regulation of mood and aggression by this neurotransmitter. Taken together with his observation on lithium and D2 receptor signaling Dr Beaulieu's research achievements may thus provide a new framework to understand the interaction between dopamine and 5-HT neurotransmission which is believed to be a cornerstone of the several psychiatric drugs such as second-generation antipsychotics.

A converging point for etiology and therapy of schizophrenia. Finally, several mutations in genes associated with schizophrenia (Akt1, Disc1, neuregulin 1) or bipolar disorder (Tph2) have been shown to affect Akt and GSK3 signaling in different cellular or animal experimental models. Thus identification by Dr. Beaulieu of a regulation of these signaling molecules by D2 receptors, antipsychotic and lithium may also provide a mechanistic point of convergence between mutations involved in mental disorders and pharmacological therapies used to manage them. Such a convergence can provide a better understanding of mental disorders and open new avenues for the development of new psychoactive drugs.

Dr. Cecilia Flores

Dr. Cecilia Flores' program of research is directed at understanding the nature of the changes induced in dopamine (DA) neurons and their connections by genetic abnormalities and by exposure to drugs or stressors at different times in life. She hopes to discover their underlying mechanisms and their implications for psychopathology. Dr. FLores completed her graduate studies in the field of behavioral neuroscience at the Center for Studies in Behavioral Neurobiology, Concordia University. During this period she became interested in plasticity within the midbrain DA system in both mature and developing brains. Alterations in DA function are symptomatic of a variety of changes in motivation and psychopathology.

Because of her background and training, Dr. Flores has been able to apply an interdisciplinary approach to her studies. While working towards the Ph.D. at Concordia with Dr. Jane Stewart, Dr. FLores began to use neuroanatomical techniques to study the role of neurotrophic factors in the long-lasting changes in behavioral activity and in the functioning of the DA system induced by exposure to stimulant drugs of abuse. As a CIHR postdoctoral fellow, in the laboratory of Dr. Joseph Coyle, Harvard Medical School, she worked on studies in rats and mice related to the possible role of glutamate/DA interactions in the etiology of schizophrenia. Following that she held an NSERC postdoctoral fellowship in Dr. Timothy Kennedy's laboratory at the Montreal Neurological Institute where she explored the idea that developmental variations in the function of the guidance cue, netrin-1, might result in altered development of DA circuitry and influence DA function in the adult. Netrin-1 organizes brain connectivity during development but continues to be expressed in the adult. In her first set of studies she found that netrin-1 receptor-deficient mice (heterozygotes) showed profound changes in DA function and in, in turn, in DA-related behaviors (Flores et al, 2005). This set of findings opened up two related research directions. The first was to study the role of netrins in the development of the DA system itself, and in related behaviors. The second was to study the possibility that netrins play a role in the modifications in DA function and behavior brought about by exposure to drugs, stressors and other insults in the adult animal.

Abnormalities occurring during brain development may be responsible for adult alterations in DA neurotransmission in the medial prefrontal cortex (mPFC) and ventral striatum (nucleus accumbens, NAcc). Such abnormalities have been linked to psychiatric disorders, including schizophrenia, where under- or malfunction of mPFC DA contributes to cognitive symptoms and where sensitized mesolimbic DA function contributes to psychotic symptoms. It is thought that genetic predisposing factors and adverse environmental events bring about subtle variations in the normal course of the development of DA neurons, and of the regions they innervate, leading to cognitive and behavioral abnormalities in the adult. How these factors exert these effects is unknown.

Netrin-1, a member of the mammalian netrin protein family, is a bifunctional guidance cue that, by attracting or repelling growing neurites, directs them toward their appropriate targets. Dr. Flores is working on the idea that developmental variations in the function of DCC (deleted in colorectal cancer), a netrin-1 receptor highly expressed by DA neurons, alter the development of mesocortical and mesolimbic DA circuitry and influence DA function in adulthood. Using dcc heterozygous (+/-) mice, she has found that adult mice have sizeable increases in tissue levels of DA in the mPFC, both basal and amphetamine (AMPH)-induced extracellular concentrations of DA, but decreased AMPH-induced DA activity in nucleus accumbens NAcc. Correspondingly, adult dcc +/- mice exhibit blunted AMPH-induced locomotion and reward, resistance to AMPH-induced deficits in sensorimotor gating, and do not develop sensitization to AMPH when treated repeatedly. Significantly, these behavioral effects are not seen before puberty. These findings suggest that DCC-deficient mice have greater mPFC DA function which may serve to protect them from NAcc DA dysfunction and behaviors usually observed in developmental animal models of schizophrenia or following chronic exposure to drugs of abuse.

Recent studies from her laboratory are showing that compared to wild-type mice, adult dcc +/- mice exhibit structural and molecular changes in mPFC, but not in NAcc, that indicate altered DA circuitry in this region. In another set of studies carried out in wild-type mice she found that the pattern of expression of netrin-1 receptors by mesocortical DA neurons shifts dramatically during the peri-pubertal period from that seen in the pre-natal and post-natal periods (Labelle-Dumais et al. 2009). These findings may be related to the fact that the behavioral, neurochemical, and neuroanatomical phenotypes observed in adult dcc +/- mice are evident only after puberty (Grant et al. 2009). This research is ongoing.

Her work has led to a number of collaborations with researchers at the Douglas Research Center who are working on the influence of early brain injury (Flores et al. 2009) and infection (Aguilar-Valles et al, 2009) on the development of abnormalities in DA function in the adult. It is hoped that these findings and ongoing work will provide information about molecular mechanisms underlying individual differences in susceptibility to psychopathology.

Studies in the Adult

Stimulant drugs, such as AMPH, induce locomotor-activating and rewarding effects by increasing striatal extracellular DA levels. These behavioral and neurochemical effects become sensitized upon repeated drug administration. Sensitization develops gradually and is long-lasting, suggesting alterations in the organization of DA circuitry. Consistent with the evidence that netrin-1 receptors are expressed within the midbrain DA system in the adult brain, Dr. Flores has shown a potential role for netrin-1 in drug-induced DA plasticity in the adult. She has shown that a behaviorally sensitizing treatment with the stimulant drug amphetamine results in a significant and enduring upregulation of DCC expression in the VTA, an effect that is prevented by blockade of the NMDA glutamate receptor (Yetnikoff et al. 2007). Interestingly, adult mice with reduced levels of DCC do not develop sensitization to the behavioral effects of AMPH when treated repeatedly, do not exhibit AMPH-induced upregulation of DCC in the VTA and, intriguingly, do not exhibit AMPH-induced upregulation of the dendritic spine-associated protein, spinophilin. Furthermore, blockade of DCC function directly into the VTA during AMPH pretreatment prevents the development of behavioral sensitization indicating that AMPH-induced DCC upregulation in the VTA is required for the development of DA sensitization (Yetnikoff et al. 2009).

These and ongoing studies in the adult animal are aimed at determining the mechanisms underlying the lasting effects of exposure to drugs and to stressors on the midbrain DA neurons and their connections and how these alternations leave this circuitry more vulnerable to events that subsequently activate it.

Dr. Jean Martin Beaulieu and Dr. Cecilia Flores are both undoubtedly most worthy recipients of the CCNP's 2010 Young Investigator Award. Congratulations to Drs. Beaulieu and Flores!