Role of drebrin A in dendritic spine plasticity and synaptic function

Abstract

Drebrin A is one of the most abundant neuron-specific binding proteins of F-actin and its expression is increased in parallel with synapse formation. Drebrin A is particularly concentrated in dendritic spines, postsynaptic sides of excitatory glutamatergic synapses. More recently, Ferhat and colleagues reported the functional role of drebrin A in regulating synaptic transmission. Indeed, our study showed that overexpression of drebrin A induced an increase of glutamatergic but not GABAergic synapses and resulted in the alteration of the normal excitatory-inhibitory ratio in favour of excitation in mature hippocampal neurons. Downregulation of drebrin A expression by antisense oligonucleotides resulted in the decrease of both miniature- glutamatergic and GABAergic synaptic activities without affecting the excitatory-inhibitory ratio. Studies performed in heterologous cells revealed that drebrin A reorganized the actin filaments and stabilized them and that these effects are depend upon its actin-binding domain. These results suggest that drebrin A regulates dendritic spine morphology, size and density, presumably via regulation of actin cytoskeleton remodeling and dynamics. These data demonstrate for the first time that an actin-binding protein such as drebrin A regulates both glutamatergic and GABAergic synaptic transmissions, probably through an increase of active synaptic site density for glutamatergic transmission and through homeostatic mechanisms for the GABAergic one.

Acknowledgements

This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Centre National de la Recherche Scientifique (CNRS).

Figures and Tables

Figure 1 Relative levels of DA expression control synaptic activity leading or not to the alteration of the normal excitatory-inhibitory (E/I) synaptic activity ratio. DA alterations (overexpression or underexpresssion) might result in either strengthening or weakening of synaptic transmission, which in turn could regulate the normal excitatory-inhibitory balance. In all cases, these synaptic alterations lead in synaptic dysfunction, which according to different brain regions involved, could underlies complex psychiatric disorders such as autism and mental retardation or the cognitive impairment accompanying normal aging and neurological disorders, including Epilepsy, Alzheimer's disease and Down's syndrome.