How activity-induced lasting changes in synaptic transmission are involved in learning and memory.

Activity-dependent regulation of synaptic transmission and membrane excitability are essential for long-term neuronal plasticity. They enable an animal to learn from its experience and adapt to its environment. The cerebellum plays an important role in motor learning, emotional behavior, and associative memory. We are interested in understanding how long-term changes in synaptic functioning underly learning and memory in the cerebellum. To address these questions we determine (1) how changes in the pattern of neuronal activity are able to modulate synaptic transmission; (2) how synaptic plasticity alters the activity of the cerebellar circuits; (3) whether the activity-dependent change in synaptic transmission is associated with learning and memory in the cerebellum.

Our recent work has revealed the presence of an unusual type of synaptic plasticity - one in which neuronal activity induces a very rapid change in the subunit composition of AMPA-type glutamate receptors present at the parallel fibre - stellate cell synapse in the cerebellum. This postsynaptic modification gives rise to a change in the amplitude of the synaptic current, the calcium permeability and its voltage dependence, producing a qualitative change in synaptic transmission. What is the molecular mechanism underlying this activity-dependent switch in AMPA receptor phenotype. We are currently investigating whether neuronal activity regulates the trafficking of AMPA receptors or the transcription of AMPA receptor subunits.

The excitability of a neuron is regulated by the balance of excitatory and inhibitory inputs. We have found that an excitatory transmitter can increase the release of an inhibitory transmitter and thus paradoxically produces a long-lasting enhancement of inhibitory synaptic transmission. This presynaptic modulation provides a mechanism by which activation of NMDA-type glutamate receptors can induce a long-term increase in the release of GABA and thus modify the activity of the cerebellar neuronal circuit. We use pharmacological tools and transgenic mice to investigate the molecular mechanism(s) that regulate the long-term potentiation of inhibitory transmission.