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21-06-2010 | Mental health | Article

Extracellular pathway implicated in neurobiology of mental disorders


Free abstract

MedWire News: Patients with major depressive disorder (MDD), bipolar disorder, and schizophrenia show disruption of the extracellular-regulated protein kinase (ERK) pathway, results of a post-mortem brain study show.

The findings point to the importance of neuron growth, genesis, and survival, with the researchers suggesting that “the ERK pathway may represent a new target for the development of novel pharmaceuticals for the treatment of these devastating disorders.”

Research into the neurobiology of mood disorders and schizophrenia has traditionally focused on neurotransmitter systems, note Husseini Manji (National Institute of Mental Health, Bethesda, Maryland, USA) and colleagues in the Journal of Affective Disorders.

However, a growing body of evidence suggests that these disorders are also associated with regional impairments of neuronal plasticity and resilience.

Yuan and colleagues note that the ERK pathway could be key to this plasticity. In one study pharmacological inhibition of mitogen activated protein kinase (MEK) in ERK1 knockout mice resulted in impaired reconsolidation of fear memories, despite the fact that these mice showed no cognitive deficits.

To investigate further, the researchers obtained postmortem frontal cortex samples from individuals with MDD, bipolar disorder, schizophrenia, and mentally healthy controls (15 from each group).

They used western blot analyses to measure levels of different proteins involved in the ERK pathway, namely, Rap1, B-Raf, MEK1, MEK2, ERK1/2, RSK1, CREB, NSE, and beta-actin.

Levels for most of the proteins studied were reduced in the patient groups compared with controls, although the patterns of these decreases differed.

In individuals with schizophrenia, levels of the following proteins were significantly reduced compared with controls: B-raf by 48%; MEK1 by 53%; MEK2 by 52%; RSK1 by 41%; CREB by 23%; and Rap1 by 48%.

Levels of the proteins MEK1, MEK2, CREB, and Rap1 were also significantly reduced in individuals with MDD, by 55%, 59%, 32%, and 47%, respectively.

In individuals with bipolar disorder, however, reductions reached statistical significance for only two proteins: B-raf, 43%; and MEK1, 60%.

Discussing their findings, Manji et al comment: “It is interesting to note that our results suggest a certain degree of neurodegeneration that may or may not be distinct from classic neurodegeneration observed in disorders such as Alzheimer's and Parkinson's diseases.”

MedWire ( is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

By Andrew Czyzewski

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