This presentation will focus upon the molecular basis
of motor learning in the cerebellum. The cerebellum is
an unusually good model system where it is possible to
build a comprehensive model of learning that flows from
molecules and synapses continually through cells and circuits,
culminating in behavior. Recent work from my lab using
electrophysiological and imaging techniques will be combined
with that of others to create a complete and testable
hypothesis for a form of learning in the mammalian brain.
Over the last 20 years, a series of experiments that
have used behavioral tasks together with extracellular
recording, reversible inactivation, and transgenic manipulations
have produced a strong case that the cerebellum is critical
for these forms of motor learning. In particular, LTD
and LTP of the parallel fiber-Purkinje cell synapse have
been implicated in the acquisition and extinction of eyeblink
conditioning, respectively.
The goals and objectives of the research performed in
this lab are: to provide an overview of the cerebellar
circuit and its proposed role in motor learning; to summarize
recent molecular insights into synaptic phenomena such
as long term potentiation and depression which are suggested
to underlie memory; and to look towards the future in
considering how molecular genetics can be used to ultimately
provide a test of the present comprehensive hypothesis.
This laboratory has used both electrode and optical recording
in cerebellar slice and culture model systems to explore
the molecular requirements for induction and expression
of these phenomena. In particular, we (and others) have
found that induction of LTP in the parallel fiber synapse
requires a presynaptic cascade of Ca influx/adenylyl cyclase
I/cAMP/PKA and that its expression is also presynaptic.
In contrast, induction of LTD at this synapse is triggered
by postsynaptic activation of mGluRl and AMPA receptors
together with Ca influx, resulting in activation of PKC
and consequent clathrin-mediated internalization of AMPA
receptors. In addition, inhibition of postsynaptic protein
phosphatase activity through a cascade involving NO, CGMP,
and cGMP-dependent protein kinase may be important.
Along the way, we discovered a new form of plasticity,
LTD at the climbing fiber-Purkinje cell synapse, which
was not anticipated in models of cerebellar learning and
which appears to share some induction requirements with
parallel fiber LTD. In addition, we have expanded our
analysis to include use-dependent synaptic as well as
non-synaptic plasticity in the cerebellar output structure,
the deep nuclei. At the level of basic science, these
investigations are central to understanding the cellular
substrates of information storage in a brain area where
the behavioral relevance of the inputs and outputs is
unusually well defined. In addition, these investigations
have potential clinical relevance not only for cerebellar
motor disorders, but also for disorders of learning and
memory generally.
