The Neurobiology of Bipolar Disorder: Focus on Signal Transduction Pathways and the Regulation of Gene Expression

Yarema Bezchlibnyk, BSc1, L Trevor Young, MD, PhD2

Objective: This article presents an overview of signal transduction pathways and reviews the research undertaken to study these systems in clinically relevant samples from patients with bipolar disorder (BD).

Method: We reviewed the published findings from studies of postmortem brain tissue and blood samples from patients with BD.

Results: Although the exact biochemical abnormalities have yet to be identified, the presented findings strongly suggest that BD may be due, at least in part, to abnormalities in signal transduction mechanisms. In particular, altered levels or function, or both, of G-protein a subunits and effector molecules such as protein kinase A (PKA) and protein kinase C (PKC) have consistently been associated with BD both in peripheral cells and in postmortem brain tissue, while more recent studies implicate disruption in novel second-messenger cascades, such as the ERK/MAPK pathway.

Conclusions: Despite the difficulties inherent in biochemical studies of clinically relevant tissue samples, numerous investigations have illuminated the signal transduction mechanisms in patients with BD. These studies also suggest that BD may be due to the interaction of many abnormalities. In this context, novel techniques enabling the study of gene expression promise to assist in untangling these complex interactions, through visualizing the end result of these changes at the level of gene transcription.

(Can J Psychiatry 2002;47:135–148)

Clinical Implications

Understanding the abnormalities underlying bipolar disorder (BD) may lead to a better understanding of current drug effects and novel pharmacotherapy and thus enable more effective treatment of patients with this illness.
Elucidating verifiable molecular and biochemical markers for BD may assist in developing more robust and effective patient diagnosis.
A solid understanding of signal transduction pathways and their downstream effects is relevant to all illnesses involving changes in cell signalling or gene expression.

Limitations

Currently, the biochemical and molecular abnormalities underlying BD are unknown.
The abnormalities thought to underlie BD are likely not due to a single defect.
The functional implications of the research described herein are limited by the lack of knowledge with respect to changes in gene expression associated with these disorders and the need to develop effective and accurate methods of ascertaining these alterations in clinical samples.

Key Words: signal transduction abnormalities, bipolar disorder, clinical studies, brain, gene expression

Résumé: La neurobiologie du trouble bipolaire : accent sur les voies de transduction de signal et le contrôle de l’expression génique

Bipolar disorder (BD) is a relatively common illness with episodes of mania and depression and, in most patients, a chronic recurrent course. The burden of illness was previously underappreciated; it spans a continuum from psychosocial impairment to an increased risk of suicide. Treatments available for the disorder have proliferated over the past decade and include a diverse group of agents ranging from lithium to anticonvulsant and novel antipsychotic agents. As our understanding of the specific neurobiology of BD increases, genetic susceptibility genes are increasingly seen as having clear importance in the disorder’s etiology. Neurohormonal pathways, such as the hypothalamic-pituitary-adrenal axis and classic monoaminergic neurotransmitter systems, have all been well studied in BD. A more recent focus on the role of excitatory amino acids such as glutamate has emerged with the findings that lithium can regulate reuptake of this amino acid in animal models. The intracellular mechanisms linked to these receptors provide an interesting system that may be central to BD and that has recently been intensively studied in patients with this disorder. (A list of abbreviations and acronyms used in this paper appears on page 144.)

The complexity and diversity of signal transduction pathways continues to emerge; however, several general features can be used to understand the networks. These features have allowed direct investigation in tissue samples from patients with BD. Most neurotransmitter receptors couple to guanine-nucleotide binding proteins (G-proteins). These proteins link receptors to specific enzymes that produce second messengers, or alternatively, they link to specific ion channels. The extracellular signals are integrated, amplified, and transmitted to specific intracellular enzymes, called effectors, which catalyze the production of an extensive array of cascading second messengers. In turn, these messenger molecules act on various protein kinases (1). The activation of these kinases is instrumental in regulating diverse intracellular processes, including gene expression, and in relating these to lasting neurobiological changes (1,2). Indeed, the number of findings on abnormalities in signal transduction systems in samples obtained directly from patients is growing.