Molecular Mechanisms of Synaptic Plasticity

Ippocampo (Marie) (sml)
Hippocampi can be dissociated and neurons can be cultured to be geneti­cally modified to express specific fluo­rescent proteins.

Fettina Ippocampo (Marie) (sml)
The hippocampal acute slice preparation: The hippocampus, the region where memory is stored, can be studied in vitro using electro­physiological techniques. It is composed of three principal areas: The CA1, CA3 and dentate gyrus (DG) areas.

Ippocampo infettato da Virus (Marie) (sml)
The hippocampus regions of live animals (here the dentate gyrus) can be infected by viruses expressing specific fluorescent proteins.

Memories are formed and retrieved on a daily basis. This complex brain function is crucial to our survival and known to be altered in a multitude of human pathologies, such as in mental retardation illnesses (e.g. Down Syndrome), in Alzheimer´s disease and also during normal aging. Much work in the field of Neuroscience has focused on understanding the molecular mechanisms regulating the complex neural circuit adaptations leading to memory formation and retrieval. The single units of this circuit, the neurons, are known to communicate through their synapses. The properties of these synapses have been shown to confer great plasticity (e.g. Long Term Potentiation and Long Term Depression) to the neuron in response to a given stimulus (e.g. a learning event). The main focus in my laboratory is to understand the molecular mechanisms that regulate such synaptic plasticity.

One molecular mechanism that has received particular attention is the transcription pathway that is regulated by the transcription factor CREB. It is known that this pathway is activated during synaptic plasticity and during a learning event. Little is known, however, about the neuronal adaptations resulting from such activation. To begin to investigate these adaptations, we optimized a new technique that allows in vivo expression of recombinant proteins in the rodent brain. Using viral mediated gene transfer, we can express proteins of the CREB-dependent transcription pathway in live rats and investigate the phenotypes of the infected neurons in acutely dissociated brain slices by whole-cell electrophysiology. Recently, we showed that activation of CREB leads to the formation of new synapses that contain only NMDA receptors (called silent synapses). One attractive hypothesis is that these new silent synapses are important for memory storage and/or retrieval.

Using a combination of molecular, cellular and biochemical techniques as well as in vivo viral mediated gene transfer and electrophysiology, we will continue to investigate the role of the CREB transcription pathway and related signaling molecules in the formation of synaptic plasticity and memory in health and disease. We hope that these studies will further the understanding of the molecular mechanisms regulating memory formation and shed light on the molecular defects that are responsible for the related pathologies.