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Cellular Plasticity Cascades in the Pathophysiology and Treatment of Bipolar Disorder

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Cellular Plasticity Cascades in the Pathophysiology and Treatment of Bipolar Disorder Neuropsychopharmacology REVIEWS (2008) 33, 110–133 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 ............................................................................................................................................................... REVIEW 110 www.neuropsychopharmacology.org Cellular Plasticity Cascades in the Pathophysiology and Treatment of Bipolar Disorder 1,3 2,3 2 ,1 Robert J Schloesser , Jian Huang , Peter S Klein and Husseini K Manji* 1 Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, 2 Bethesda, MD, USA; Department of Medicine (Hematology-Oncology), University of Pennsylvania School of Medicine, Philadelphia, PA, USA Bipolar disorder (BPD) is characterized by recurrent episodes of disturbed affect including mania and depression as well as changes in psychovegetative function, cognitive performance, and general health. A growing body of data suggests that BPD arises from abnormalities in synaptic and neuronal plasticity cascades, leading to aberrant information processing in critical synapses and circuits. Thus, these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters. In addition, commonly used mood- stabilizing drugs that are effective in treating BPD have been shown to target intracellular signaling pathways that control synaptic plasticity and cellular resilience. In this article we draw on clinical, preclinical, neuroimaging, and post-mortem data to discuss the neurobiology of BPD within a conceptual framework while highlighting the role of neuroplasticity in the pathophysiology and treatment of this disorder. Neuropsychopharmacology Reviews (2008) 33, 110–133; doi:10.1038/sj.npp.1301575; published online 3 October 2007 Keywords: bipolar disorder; neuroplasticity; intracellular signaling cascades; lithium; valproic acid; mood stabilizer INTRODUCTION assessing response to mood stabilizer and antidepressant medications. The monoaminergic systems are extensively Bipolar disorder (BPD) is a common, chronic, recurrent distributed throughout the network of limbic, striatal, and mental illness that affects the lives and functioning of prefrontal cortical neuronal circuits thought to support the millions of individuals worldwide. A growing number of behavioral and visceral manifestations of mood disorders recent studies indicate that for a majority of these (Drevets, 2000). Studies of cerebrospinal fluid chemistry, individuals, outcome is quite poor. High rates of relapse, neuroendocrine responses to pharmacological challenge, chronicity, lingering residual symptoms, subsyndromes, and neuroreceptor and transporter binding have demon- cognitive and functional impairment, psychosocial disabil- strated a number of abnormalities in monoaminergic ity, and diminished well-being are unfortunately common neurotransmitter and neuropeptide systems in mood occurrences in BPD (Belmaker, 2004). Furthermore, BPD is disorders (Goodwin and Jamison, 2007). a systemic disease that is frequently associated with a wide Unfortunately, these observations have not yet greatly range of physiological perturbations and medical problems, advanced our understanding of the underlying biology of including cardiovascular disease, diabetes mellitus, obesity, recurrent mood disorders, which must include an explana- and thyroid disease (Kupfer, 2005). Neurobiological studies tion for the predilection to episodic and often profound of mood disorders over the past 40 years have primarily mood disturbance that can become progressive over time. focused on abnormalities of the monoaminergic neuro- BPD likely arises from the complex interaction of multiple transmitter systems, on characterizing alterations of in- susceptibility (and protective) genes and environmental dividual neurotransmitters in disease states, and on factors, and the phenotypic expression of the disease includes not only mood disturbance, but also a constellation of cognitive, motor, autonomic, endocrine, and sleep/wake *Correspondence: Dr HK Manji, Laboratory of Molecular Pathophysio- abnormalities. Furthermore, while most antidepressants logy, Mood and Anxiety Disorders Program, National Institute of Mental exert their initial effects by increasing intrasynaptic levels Health, Porter Neuroscience Research Center, Building 35, Room 1C- 917, 35 Convent Drive, Bethesda, MD 20892, USA, Tel: + 1 301 496 of serotonin and/or norepinephrine, their clinical antide- 9802, Fax: + 1 301 480 0123, E-mail: [email protected] pressant effects are observed only after chronic adminis- 3Dr Schloesser and Dr Huang share first authorship. tration (over days to weeks), suggesting that a cascade of Received 16 July 2007; revised 1 August 2007; accepted 14 August downstream events is ultimately responsible for their 2007 therapeutic effects. These observations have led to the idea .............................................................................................................................................. Neuropsychopharmacology REVIEWS Cellular plasticity cascades in BPD RJ Schloesser et al REVIEW ............................................................................................................................................................... 111 Table 1 Putative Roles for Signaling Pathways in Mood Disorders and Nestler, 1996); furthermore, substantial life events that occur during development of the organism often have a Amplify, attenuate, and integrate multiple signals that form the basis for intracellular circuits and cellular modules greater impact than they would later in life. In recent years, research has linked mood disorders with Regulate multiple neurotransmitter and peptide systems structural and functional impairments related to neuroplas- Play critical role in cellular memory and long-term neuroplasticity ticity in various regions of the CNS. In addition, psycho- Regulate complex signaling networks that form the basis for higher order brain tropic drugs commonly used to treat these conditions target function, mood, and cognition molecules and signaling cascades implicated in the control Act as major targets for many hormones implicated in mood disorders, including of neuroplasticity. Research on the biological underpin- gonadal steroids, thyroid hormones, and glucocorticoids nings of mood disorders has therefore moved away from Act as targets for medications that are most effective in the treatment of mood focusing on absolute changes in neurochemicals such as disorders monoamines and neuropeptides, and instead has begun highlighting the role of neural circuits and synapses, and the plastic processes controlling their function. Thus, these illnesses can best be conceptualized as genetically influ- that while dysfunction within the monoaminergic neuro- enced disorders of synapses and circuits rather than simply transmitter systems is likely to play an important role in as deficits or excesses in individual neurotransmitters. The mediating some facets of the pathophysiology of BPD, it integration of knowledge derived from different physiolo- likely represents the downstream effects of other, more gical and phenomenological levels continues to help move primary abnormalities in signaling pathways (Table 1) us toward a more conceptual understanding of the etiology (Goodwin and Jamison, 2007) (Figure 1a). and pathophysiology of BPD. As we review in this paper, a growing body of data supports the contention that BPD Why Consider Plasticity Cascades as Playing arises from abnormalities in cellular plasticity cascades, a Central Role in the Pathophysiology and leading to aberrant information processing in synapses and Treatment of BPD? circuits mediating affective, cognitive, motoric, and neuro- vegetative functions (Catapano et al, in press; Post, 2007; Plasticity, the ability to undergo and sustain change, is Young, 2007). Indeed, in a recent whole-genome association essential for the proper functioning of our nervous system. study of BPD, all of the highly significant associations This capacity for change allows organisms to adapt to implicated signaling cascades (Baum et al, 2007). complex alterations in both their internal and external The role of cellular signaling cascades has the potential to environments, a feature fundamentally important for explain much of the complex neurobiology of BPD (Good- survival and reproduction. Besides the evident need for win and Jamison, 2007). Cellular signaling cascades regulate significant adaptation mechanisms in learning and memory the multiple neurotransmitter and neuropeptide systems as well as physiological homeostasis, all complex behavioral implicated in the disorder, and are targets for the most phenomenaFincluding mood and emotionFare dynamic effective treatments. Signaling pathways are also targets for processes that rely on plastic neural circuitry. The biological hormones that have been implicated in the pathophysiology basis of this capacity to adapt encompasses a diverse set of of BPD. The highly integrated monoamine and prominent cellular and molecular mechanisms that fall under the broad neuropeptide pathways are known to originate and project term ‘neuroplasticity’. In this paper, we make the distinc- heavily to limbic-related regions such as the hippocampus, tion between synaptic plasticity and neuroplasticity. hypothalamus, and brain stem, which are likely associated Synaptic
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