Abstract
Cerebellar GABAergic inhibitory transmission between interneurons and Purkinje cells (PCs) undergoes a long-lasting enhancement following different stimulations, such as brief depolarization or activation of purinergic receptors of postsynaptic PCs. The underlying mechanisms, however, are not completely understood. Using a peak-scaled non-stationary fluctuation analysis, we therefore aimed at characterizing changes in the electrophysiological properties of GABAA receptors in PCs of rat cerebellar cortex during depolarization-induced “rebound potentiation (RP)” and purinoceptor-mediated long-term potentiation (PM-LTP), because both RP and PM-LTP likely depend on postsynaptic mechanisms. Stimulation-evoked inhibitory postsynaptic currents (eIPSCs) were recorded from PCs in neonatal rat cerebellar slices. Our analysis showed that postsynaptic membrane depolarization induced RP of eIPSCs in association with significant increase in the number of synaptic GABAA receptors without changing the channel conductance. By contrast, bath application of ATP induced PM-LTP of eIPSCs with a significant increase of the channel conductance of GABAA receptors without affecting the receptor number. Pretreatment with protein kinase A (PKA) inhibitors, H-89 and cAMPS-Rp, completely abolished the PM-LTP. The CaMKII inhibitor KN-62 reported to abolish RP did not alter PM-LTP. These results suggest that the signaling mechanism underlying PM-LTP could involve ATP-induced phosphorylation of synaptic GABAA receptors, thereby resulting in upregulation of the channel conductance by stimulating adenylyl cyclase-PKA signaling cascade, possibly via activation of P2Y11 purinoceptor. Thus, our findings reveal that postsynaptic GABAA receptors at the interneuron-PC inhibitory synapses are under the control of two distinct forms of long-term potentiation linked with different second messenger cascades.
Highlights
Synaptic plasticity, such as long-term potentiation (LTP) or long-term depression, is a potential cellular basis of learning and memory
We found that: (1) depolarization-induced rebound potentiation (RP) of GABAergic transmission at cerebellar interneuron-Purkinje cells (PCs) inhibitory synapses could be caused by an increase in the number of synaptic GABAA receptors without changes in the receptor channel conductance; and (2) activation of purinoceptors by adenosine 5’-triphosphate (ATP) resulted in another form of plasticity, purinoceptor-mediated long-term potentiation (PM-LTP), at the GABAergic synapses through an increment of GABAA receptor conductance without discernible changes in the receptor channel number
It is highly likely that cerebellar interneuron-PC inhibitory synapses undergo profound synaptic plasticity caused by at least two distinct postsynaptic mechanisms: one is PM-LTP, namely ATP-induced enhancement of GABAergic transmission, that could be mediated by cAMP-protein kinase A (PKA)-dependent upregulation of single GABAA receptor channel conductance in PCs, and the other RP, namely postsynaptic depolarization-induced enhancement of GABAergic transmission, that could recruit the insertion of novel GABAA receptors into the synaptic sites between interneurons and PCs
Summary
Synaptic plasticity, such as long-term potentiation (LTP) or long-term depression, is a potential cellular basis of learning and memory. In the LTP at excitatory glutamatergic synapses, CaMKII is reported to affect AMPA receptors via at least two distinct mechanisms. Lüthi et al [8] reported that among hippocampal CA1 pyramidal cells that developed LTP and the subsequent depotentiation, only 60% of them were associated with an alternation in receptor conductance.
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