A central hypothesis of modern neurobiology is that memory is stored through use-dependent changes in synaptic strength. Most work in this area has focused upon long-term potentiation and depression (LTP & LTD) of excitatory, glutamatergic synapses. One limitation of this approach is that the brain regions where LTP/LTD are most often studied, such as the hippocampus, receive information that is so complex that its content cannot be easily characterized. In contrast, in the cerebellum it has been possible to propose a """"""""circuit diagram"""""""" for some simple forms of learning such as adaptation of the vestibulo-ocular reflex, and associative eyeblink conditioning. For example, it is possible to assign the conditioned (CS) and unconditioned stimuli (US) in associative eyeblink conditioning to specific pathways (mossy and climbing fibers, respectively). Over the last 20 years, a series of experiments that have used behavioral tasks together with extracellular recording, lesion and reversible inactivation have produced a strong case that the cerebellum is critical for these forms of motor learning. However, the precise synaptic location of the cerebellar engram has been elusive, with some studies favoring the synapses received by the Purkinje cell while others have implicated those received by the deep cerebellar nuclei (DCN). While the cellular electrophysiology of the Purkinje cell has been widely investigated, there are few studies which have examined the DCN. Recently, this laboratory has performed intracellular recordings from neurons of the DCN using a brain slice preparation. These have shown that activation of GABAergic Purkinje cell-to-DCN synapses (with a burst and pause stimulus that mimics natural firing patterns) results in a prominent rebound depolarization and associated spike burst which are evoked upon release from hyperpolarization, providing a mechanism by which inhibitory inputs can drive postsynaptic excitation. In these cells, LTP can be elicited by short, high-frequency.trains of IPSPs that reliably evoke a rebound depolarization in the DCN neurons. LTD is induced if the same protocol is applied while the amount of postsynaptic excitation is reduced (by postsynaptic hyperpolarization or an internal Na channel blocker). The polarity of the change in synaptic strength is correlated with the amount of rebound depolarization-evoked spike firing and the amplitude of the resulting postsynaptic Ca transient. In addition, we have preliminary data demonstrating LTD of the glutamatergic mossy fiber-DCN synapse. The present proposal seeks to build upon these initial results by addressing the following questions: What specific conductances contribute to the intrinsic excitability of DCN cells and how are they altered by neuromodulators such as acetylcholine and serotonin? What are the basic computational properties of LTP and LTD at the Purkinje cell-DCN synapse (optimal induction, saturability, reversibility, input specificity)? What Ca signals and second messenger systems are required for induction of LTP and LTD at the Purkinje cell-DCN synapse? What are the requirements for the induction of LTP and LTD at the mossy fiber-DCN synapse? At the level of basic science, these investigations are central to understanding the cellular substrates of information storage. In addition, they have potential clinical relevance for both cerebellar motor disorders and disorders of learning and memory generally.
| Zhang, Wei; Linden, David J (2006) Long-term depression at the mossy fiber-deep cerebellar nucleus synapse. J Neurosci 26:6935-44 |
| Zhang, Wei; Shin, Jung Hoon; Linden, David J (2004) Persistent changes in the intrinsic excitability of rat deep cerebellar nuclear neurones induced by EPSP or IPSP bursts. J Physiol 561:703-19 |
| Aizenman, Carlos D; Huang, Eric J; Linden, David J (2003) Morphological correlates of intrinsic electrical excitability in neurons of the deep cerebellar nuclei. J Neurophysiol 89:1738-47 |
| Hansel, C; Linden, D J; D'Angelo, E (2001) Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum. Nat Neurosci 4:467-75 |
