Bipolar disorder: involvement of signaling cascades and AMPA receptor trafficking at synapses

There is increasing evidence that severe mood disorders are associated with impairment of structural plasticity and cellular resilience. Cumulative data demonstrate that mood stabilizers regulate intracellular signaling cascades, including protein kinase C (PKC), PKA, mitogen-activated protein (MAP) kinase, glycogen synthase kinase 3-β (GSK3-β) and intracellular calcium, which are signaling pathways that regulate synaptic plasticity. In this context, it is noteworthy that a growing body of data indicates that the glutamatergic system, has a major role in neuronal plasticity and cellular resilience, might be involved in the pathophysiology and treatment of mood disorders. AMPA glutamate-receptor trafficking is important in synaptic plasticity and might play crucial roles in maintaining critical neuronal circuits associated with mood. Two clinically effective, structurally dissimilar, antimanic agents, lithium and valproate (VPA), down-regulate synaptic expression of AMPA receptor subunit GluR1 in hippocampus in chronically treated rats. This reduction in synaptic GluR1 by lithium and VPA is due to attenuated phosphorylation of GluR1 at a specific PKA site (residue 845 of GluR1), which is crucial for AMPA receptor insertion. By contrast, imipramine, which can provoke mania, increases synaptic expression of GluR1 in the hippocampus in vivo. Furthermore, there is ample evidence from preclinical and clinical research that the glutamatergic system is involved in the pathophysiology of mood disorders and that many of the somatic treatments used for mood disorders including antidepressants, mood stabilizers, atypical antipsychotic drugs and electroconvulsive therapy have both direct and indirect effects on the glutamatergic system. Given these findings, further research with medications that specifically affect the glutamatergic system is warranted. Recent studies in our lab have shown that riluzole, a FDA approved medicine that regulates the glutamatergic system, shows antidepressant efficacy in unipolar and bipolar depression. These studies indicate that regulation of glutamate-mediated synaptic plasticity might play a role in the treatment of mood disorders, and raise new avenues for novel therapies for this devastating illness.

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Regulation of cellular plasticity and resilience by mood stabilizers: the role of AMPA receptor trafficking

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2004.6.2/jdu ◽

2004 ◽

Vol 6 (2) ◽

pp. 143-155

Keyword(s):

Mood Disorders ◽

Neural Plasticity ◽

Neuronal Plasticity ◽

Brain Volume ◽

Critical Role ◽

Receptor Trafficking ◽

Mood Stabilizers ◽

Brain Areas ◽

Cellular Resilience

There is increasing evidence from a variety of sources that severe mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamaiergic system (which is known to play a major role in neuronal plasticity and cellular resilience) may be involved in the pathophysiology and treatment of mood disorders. Glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) GluR1 receptor trafficking plays a critical role in regulating various forms of neural plasticity. It is thus noteworthy that recent studies have shown that structurally dissimilar mood stabilizers lithium and valproate regulate GluR1 receptor subunit trafficking and localization at synapses. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raises the possibility that agents more directly affecting synaptic GluR1 represent novel therapies for these devastating illnesses.

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Enhancing synaptic plasticity and cellular resilience to develop novel, improved treatments for mood disorders

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2002.4.1/jquiroz ◽

2002 ◽

Vol 4 (1) ◽

pp. 73-92

Keyword(s):

Synaptic Plasticity ◽

Cell Survival ◽

Signaling Pathways ◽

Mood Disorders ◽

Map Kinases ◽

Adenosine Monophosphate ◽

Mood Stabilizers ◽

Cellular Mechanisms ◽

Cellular Resilience

There is mounting evidence that recurrent mood disorders - once considered "good prognosis diseases"- are, in fact, often very severe and life-threatening illnesses. Furthermore, although mood disorders have traditionally been conceptualized as neurochemical disorders, there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes ofglia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggest that mood disorders are associated with impairments of synaptic plasticity and cellular resilience. In this context, it is noteworthy that there is increasing preclinical evidence that antidepressants regulate the function of the glutamatergic system. Moreover, although clearly preliminary, the available clinical data suggest that attenuation of N-methyl-D-aspartate (NMDA) function has antidepressant effects. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressant agents. Antidepressants and mood stabilizers indirectly regulate a number of factors involved in cell survival pathways, including cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), the antiapoptotic protein bcl-2, and mitogen-activated protein (MAP) kinases, and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects. There is much promise for the future development of treatments that more directly target molecules in critical CNS signaling pathways regulating synaptic plasticity and cellular resilience. These will represent improved long-term treatments for mood disorders.

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