The striatum is a collection of several nuclei involved in a variety of behaviors and brain diseases, including stimulus-response learning in experimental animals, drug addiction, various forms of psychoses, Huntington's and Parkinson's diseases. Synaptic mechanisms governing neural adaptations in the striatum are still poorly understood. We have recently demonstrated that the extracellular-signal regulated kinase (ERK) pathway is a major determinant of long-term plasticity and memory formation in this brain region. However, the molecular links between glutamatergic and dopaminergic receptors and intracellular signalling in the striatum are at present not characterized. By means of genetic manipulation in the mouse striatum we show that the neuronal-specific Ras exchange factor RasGRF1 is necessary for both glutamate- and dopamine-dependent ERK activation and immediate early gene expression. Consequently, by modulating RasGRF1 activity in vivo we observe dramatic alterations in the process of long term memory (LTM) formation, as revealed by striatum-specific learning tests. Finally, this phenotype is consistent with a clear involvement of RasGRF1 in striatal long term potentation (LTP). Our results suggest a crucial function of RasGRF1 in modulating ERK-dependent neuronal signalling in the striatum and open new perspectives for treatment of brain diseases associated to striatal dysfunction.
Ras-grf1 regulates striatum-dependent behavioural plasticity, long term synaptic signalling and responses to drugs of abuse
GIUSTETTO, Maurizio;
2004-01-01
Abstract
The striatum is a collection of several nuclei involved in a variety of behaviors and brain diseases, including stimulus-response learning in experimental animals, drug addiction, various forms of psychoses, Huntington's and Parkinson's diseases. Synaptic mechanisms governing neural adaptations in the striatum are still poorly understood. We have recently demonstrated that the extracellular-signal regulated kinase (ERK) pathway is a major determinant of long-term plasticity and memory formation in this brain region. However, the molecular links between glutamatergic and dopaminergic receptors and intracellular signalling in the striatum are at present not characterized. By means of genetic manipulation in the mouse striatum we show that the neuronal-specific Ras exchange factor RasGRF1 is necessary for both glutamate- and dopamine-dependent ERK activation and immediate early gene expression. Consequently, by modulating RasGRF1 activity in vivo we observe dramatic alterations in the process of long term memory (LTM) formation, as revealed by striatum-specific learning tests. Finally, this phenotype is consistent with a clear involvement of RasGRF1 in striatal long term potentation (LTP). Our results suggest a crucial function of RasGRF1 in modulating ERK-dependent neuronal signalling in the striatum and open new perspectives for treatment of brain diseases associated to striatal dysfunction.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
