LONG-TERM SYNAPTIC PLASTICITY IN MOUSE CEREBELLAR STELLATE CELLS
Open Access
- Author:
- Sun, Lu
- Graduate Program:
- Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 09, 2009
- Committee Members:
- Si Qiong Liu, Dissertation Advisor/Co-Advisor
Si Qiong Liu, Committee Chair/Co-Chair
Matthew Whim, Committee Member
Bernhard Luscher, Committee Member
Steven Schiff, Committee Member
Gong Chen, Committee Member - Keywords:
- calmodulin
action potential
extrasynaptic
NMDA receptor
PICK
PKC
AMPA receptor
synaptic plasticity
GABAergic interneuron
cerebellum
protein synthesis
electrophysiology - Abstract:
- The cerebellum is a brain structure essential for motor control and coordination, as well as motor learning and memory. The highly organized anatomy of the cerebellum makes it a good model for the study of network function. As the only output of the cerebellar cortex, Purkinje cells are considered as the cellular basis for certain types of motor learning. Purkinje cells receive excitatory synaptic inputs from parallel fibers and climbing fibers, and inhibitory inputs from GABAergic interneurons located at the molecular layer of the cerebellum. Since the activity of Purkinje cells is largely regulated by the synaptic integration, knowledge about cerebellar granule cells and interneurons is necessary for the understanding of the mechanism of motor learning and memory. Interneurons including stellate cells and basket cells obtain afferent excitatory inputs from parallel fibers and project inhibitory inputs onto Purkinje cells, and thus form a feed-forward inhibition network. The inhibition from the interneurons counteracts the excitatory effects from parallel fibers and prevents the Purkinje cells from being over excited. However, the synaptic plasticity of the interneurons remains elusive. Using stellate cell as a model, we investigated the function of glutamate receptors in the synaptic plasticity in interneurons and the consequent impact on the pattern of GABA release from interneuron axonal terminals, which directly determines the inhibition of Purkinje cells. We observed that the activation of extrasynaptic NMDA receptors could induce a new form of synaptic plasticity at the parallel fiber-to-stellate cell synapse, including a subtype switch of AMPA receptors from naturally GluR2-lacking (Ca2+-permeable) to GluR2-containing (Ca2+-impermeable). This plasticity is probably postsynaptically induced and requires protein kinase C (PKC) and the activity of protein interacting with PRKCA 1 (PICK1). In addition, previous studies showed that the activation of NMDA receptors directly triggered a long-lasting potentiation of GABA release at axonal terminals. Our work about the characterization of NMDA receptors in stellate cells suggested the possible expression of NR2B and NR2D subunits. However, blockade of single subtype of NMDA receptors did not affect the basal level of GABA release. Changes in synaptic transmission would alter the excitability of a cell and therefore affect the action potential firing pattern. We explored if action potential firing would in return regulate the synaptic efficacy. We found that blockade of spontaneous action potentials (sAPs) in stellate cells induced an increased expression of GluR2-containing AMPA receptors at the parallel fiber-to-stellate cell synapse. This effect might be transcription-independent, but requires intact protein synthesis machinery. Moreover, inhibition of calmodulin mimicked the effect of sAP blockade, indicating the sAP blockade-induced GluR2 expression may be mediated by a reduced calmodulin activity. Our study revealed mechanisms underlying long-term plasticity of AMPAR subtype at the parallel fiber-to-stellate cell synapse, and the potential functional significance. Our findings would gain the insight into cerebellar interneuron functions and their contribution to motor learning and memory.