Mood stabilizers and the cell biology of neuronal growth cones Britta J. Eickholt a , Robin S.B. Williams b , Adrian J. Harwood c, * a Molecular Neurobiology Group, MRC Centre for Developmental Neurobiology, King’s College London, London SE1 1UL, UK b Department of Biology, Wolfson Institute for Biomedical Research, Cruciform Building, University College London, London WC1 E6BT, UK c MRC Laboratory for Molecular Cell Biology, Department of Biology, University College London, London WC1 E6BT, UK Abstract Cultured neurons present an opportunity to study the developmental processes that construct the nervous system. Recent results have shown that the mood stabilizers lithium, valproic acid and carbamazepine cause morphological changes to the growth cones of developing neurons. These types of experiment, however, may present more than a simple method of studying mood stabilizer action in neuronal tissue. As a small amount of neurogenesis is present in the adult brain, it is possible that mood stabilizers directly act upon axonal growth, guidance and branching of developing neurons to alter the neuronal architecture. In this review, we will discuss the cell biology of neuronal growth cones and consider how mood stabilizers could target growth cone behaviour. q 2004 Association for Research in Nervous and Mental Disease. Published by Elsevier B.V. All rights reserved. Keywords: Neuronal growth cone; Bipolar mood disorder; Lithium; Valproic acid; Carbamazepine; GSK3; Inositol depletion; Phospholipids 1. Introduction More than a century ago, Ramon y Cajal described growth cones at the ends of developing axons, concluding that they are ‘endowed with amoeboid movements’, which respond to chemical signals in the same manner as blood leukocytes [1]. Since that time, neuronal growth cones have offered an accessible means to examine the cell biology of developing neurons. However, the study of growth cones may be more than just a convenient method of observing neuronal cell behaviour. The correct pattern of axonal and dendritic growth is mediated through the response of individual growth cones to extracellular guidance cues. Without the ability of growth cones to read these signals and translate them into the correct pattern of axonal and dendritic projections, it would be impossible to form the fully functional nervous system. It is not hard to imagine the effect that even a subtle change in growth cone motility and chemotaxis could have on the integrity of the neural network, growth cones therefore could offer a novel targets for mood stabilizer drugs. In this review we will examine the cell biology of neuronal growth cones and briefly discuss what is currently known about growth cone motility and chemotaxis. We will then describe recent studies which show that a number of mood stabilizers affect growth cone behaviour, and consider what this may mean for the origins of bipolar disorder and mechanisms of drug action. 2. Neuronal development, growth cones and axon branching Mature neurons integrate synaptic input at their dendrites and then relay the signal along their axons to spatially distinct regions of synaptic output. As long distances may separate input and output sites, neurons develop an extremely polarized morphology (Fig. 1). This is achieved during neuronal development by growth of neurites from the cell body that go on to form the axon and dendrites. All neurites, axons and dendrites elongate by growth at their distal end in a morphological distinct region known as the growth cone. However, growth cones are not merely areas of active growth but in fact determine axonal and dendritic structure. Mature dendrites and axons also tend to be branched. Branching is particularly extensive for the dendrites 1566-2772/$ - see front matter q 2004 Association for Research in Nervous and Mental Disease. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.cnr.2004.09.011 Clinical Neuroscience Research 4 (2004) 189–199 www.elsevier.com/locate/clires * Corresponding author. Tel.: C44 20 7679 7257; fax: C44 20 7679 7805. E-mail address: a.harwood@ucl.ac.uk (A.J. Harwood).