Cellular Substrates of Cerebellar Information Storage

Johns Hopkins University, Baltimore MD

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by the applicant): A central hypothesis of modem[unreadable] neurobiology is that memory is stored through use-dependent changes in synaptic[unreadable] strength. Most work in this area has focused upon long-term potentiation and[unreadable] depression (LiP and LTD) of glutamatergic synapses. One limitation of this[unreadable] approach is that the brain regions where LTP and LTD are most often studied,[unreadable] such as the hippocampus, receive information that is so complex that its[unreadable] content cannot be easily characterized. In contrast, in the cerebellum it has[unreadable] been possible to propose a 'circuit diagram" for some simple forms of learning[unreadable] such as associative eyeblink conditioning and vestibulo-ocular reflex[unreadable] adaptation. For example, it is possible to assign the conditioned (CS) and[unreadable] unconditioned stimuli (US) in associative eyeblink conditioning to specific[unreadable] pathways (the mossy/parallel fiber system and climbing fibers, respectively).[unreadable] Over the last 20 years, a series of experiments which have used behavioral[unreadable] tasks together with extracellular recording, reversible inactivation and[unreadable] transgenic manipulations have produced a strong case that the cerebellum is[unreadable] critical for these forms of motor learning. In particular, LTD and LTP of the[unreadable] parallel fiber-Purkinje cell synapse have been implicated in acquisition and[unreadable] extinction of eyeblink conditioning, respectively. In recent years, this[unreadable] laboratory has used both electrode and optical recording in cerebellar slice[unreadable] and culture model systems to explore the molecular requirements for induction[unreadable] and expression of these phenomena. In particular, we (and others) have found[unreadable] that induction of LiP in the parallel fiber synapse requires a presynaptic[unreadable] cascade of Ca influx/adenylyl cyclase JJcAMP/PKA and that its expression is[unreadable] also presynaptic. In contrast, induction of LTD at this synapse is triggered by[unreadable] postsynaptic activation of mGluRl and AMPA receptors together with Ca influx,[unreadable] resulting in activation of PKC and consequent clathrin-mediated internalization[unreadable] of AMPA receptors. Along the way, we discovered a new form of plasticity, LTD[unreadable] at the climbing fiber-Purkinje cell synapse, which was not anticipated in[unreadable] models of cerebellar learning and which appears to share some induction[unreadable] requirements with parallel fiber LTD. We propose additional[unreadable] electrophysiological experiments to address the following central questions.[unreadable] Which proteins of the secretory apparatus are modulated by PKA to produce the[unreadable] increase in glutamate release that underlies expression of parallel fiber LIP?[unreadable] During LTD induction at parallel fiber synapses, what are the events which link[unreadable] PKC activation with AMPA receptor internalization? Can climbing fiber LTD be[unreadable] induced using patterns of stimulation that more closely approximate natural[unreadable] signals recorded in vivo? What are the consequences of climbing fiber LTD for[unreadable] the function of the Purkinje cells and the cerebellar cortical circuit? Are[unreadable] climbing fiber-evoked Ca signals altered? Is climbing fiber LTD expressed[unreadable] presynaptically or postsynaptically? Can it be detected with recordings of[unreadable] climbing fiber-evoked glutamate transporter currents in the Purkinje cell? Can[unreadable] it be blocked with manipulations that interfere with clathrin-mediated[unreadable] internalization of AMPA receptors (as previously seen with parallel fiber LTD)?[unreadable] At the level of basic science, these investigations are central to an[unreadable] understanding the cellular substrates of information storage. In addition, they[unreadable] have potential clinical relevance for both cerebellar motor disorders and[unreadable] disorders of learning and memory generally.[unreadable]