We all know that as part of our
daily lives we are constantly interacting
with our environment, learning, adapting,
making new memories, and alas, forgetting
as well. The field of synaptic plasticity
is concerned with how neuronal connections
change to meet these demands. My
lab is concerned with understanding
the molecular events responsible
for the changes in synaptic strength
that underlie learning, memory and
adaptive behaviors. By understanding
this process in molecular detail
and identifying when these processes
have gone awry in neurological diseases,
we will establish the necessary framework
to then target these processes for
therapeutic interventions.
The approach we take to pursue these questions is to study synaptic function
using cellular electrophysiological recording techniques. We use in vitro preparations
such as cultured neurons and acute brain slice preparations. In order to identify
molecular candidates and test structure/function predictions, we use a variety
of molecular biology techniques that enable us to molecularly manipulate the
synapses we are studying.
One major area of interest is in understanding the molecular basis of
presynaptic forms of plasticity. Most recently, we have been studying RIMs,
a family of large scaffold proteins that localize to the presynaptic active
zone. Studies of RIM1α knockout mice have demonstrated roles for RIM
in basal neurotransmission, short term plasticity and long term plasticity.
These mice also exhibit learning disabilities in behavioral paradigms. RIMs
are predicted to integrate the activities of a wide variety of presynaptic
proteins by virtue of their multitude of protein-protein interactions. Through
the study of the RIM family of proteins, we hope to understand the molecular
mechanisms of presynaptic plasticity, the functional significance of these
forms of plasticity to the organism as a whole, and lastly, how to target RIM
or its interacting proteins for therapeutic interventions in candidate neurological
diseases.
A second major area of interest is in identifying abnormalities of synaptic
plasticity in the basal ganglia associated with neurological disease.
We have developed novel genetic tools to study plasticity in the basal
ganglia circuitry and are using these tools in mouse models of dystonia and
OCD.
