Evaluation of cytoskeleton dynamics in neuronal development in STOP knockout mice

BISBAL M., PERIS L., ANDRIEUX A.

Ginebra

Simposio; 1st Roche Symposium of the Postdoctoral Fellowship Program; 2010

Neurons are highly polarized cells with two molecular and functional distinct domains that emerge from the cell body: a single thin, long axon, which transmits signals, and multiple shorter dendrites, which are specialized to receive signals. The ability of neurons to polarize is crucial for synaptic transmission, and knowledge of the mechanisms that govern neuronal polarization and dendritic development are fundamental to our understanding of neural development, plasticity and neurodegenerative diseases. The principal molecular event that regulates neuronal polarization, includes actin dynamics, microtubule stabilization, and polarized membrane traffic. Alterations of microtubule dynamics or stability have been involved in several neurodegenerative pathologies and in some cases the alterations have been proposed to be causal e.g. the abnormal modifications of the microtubule associated protein Tau in Alzheimer disease. Dr. Andrieux laboratory has provided one of the first experimental evidence for a role of microtubules in mental functions by developing a mouse model deficient for a microtubule associated proteins known as STOPs. STOP-deficient mice exhibited severe alterations of brain functions with neurotransmission anomalies and sensorimotor gating impairment, associated with severe behavioral deficits that react positively to antipsychotic drugs after chronic treatments. The STOP-null mice also show global reduction of the brain mass, associated with widespread deficits in axonal extensions, whereas the number of neurons seems unaffected, an observation similar to post-mortem observation in patients with schizophrenia. Regarding this it has been proposed that epothilone D, a microtubule stabilizer drug, could alleviate behavioural and synaptic defects in STOP-deficient mice.  In hippocampal pyramidal neurons in culture, our preliminary data shows that in vitro STOP-null neurons differentiate prematurely and neurites have an abnormal morphology. STOP-null neurons also present alterations in vesicle trafficking, particularly, in retrograde movements. This atypical neuronal differentiation in the absence of STOPs proteins may be related to abnormal control of microtubules and actin dynamics. Bering in mind all these considerations, the aim and the proposal of this project is to evaluate microtubules and actin dynamics during axonal differentiation and dendritic spine formation in STOP-deficient mice and to analyze the role of STOPs proteins in synaptic plasticity, all events that are defective in neuronal pathologies. Altogether this project will allow a better understanding of how microtubules dynamic is involved in neuronal plasticity, propose potential molecular targets involved in the modulation of cytoskeletal dynamic parameters and allow us understanding the precise role of microtubule and actin cytoskeleton in neuronal and psychiatric disease. Finally, finding targets that modulate cytoskeletal dynamics might allow successful treatment of pathologies where synaptic connectivity is dysfunctional, like schizophrenia.