Abstract
The roles of myelin in maintaining axonal integrity and action potential (AP) propagation are well established, but its role in synapse maintenance and neurotransmission remains largely understudied. Here, we investigated how Purkinje axon myelination regulates synaptic transmission in the Purkinje to deep cerebellar nuclei (DCN) synapses using the Long Evans Shaker (LES) rat, which lacks compact myelin and thus displays severe locomotion deficits. DCN neurons fired spontaneous action potentials (APs), whose frequencies were dependent on the extent of myelin. In the LES cerebellum with severe myelin deficiency, DCN neurons were hyper-excitable, exhibiting spontaneous AP firing at a much higher frequency compared to those from wild type (LE) and heterozygote (LEHet) rats. The hyper-excitability in LES DCN neurons resulted from reduced inhibitory GABAergic inputs from Purkinje cells to DCN neurons. Corresponding with functional alterations including failures of AP propagation, electron microscopic analysis revealed anatomically fewer active zones at the presynaptic terminals of Purkinje cells in both LEHet and LES rats. Taken together, these studies suggest that proper axonal myelination critically regulates presynaptic terminal structure and function and directly impacts synaptic transmission in the Purkinje cell-DCN cell synapse in the cerebellum.
Highlights
Myelin sheaths wrap around axons to create electrical insulation, increasing efficiency of action potential (AP) conduction and maintenance and protection of axons from damage due to injury or disease[1,2,3]
To determine whether the reduction in GABAA receptor activation seen in Long Evans Shaker (LES) deep cerebellar nuclei (DCN) cells was due to reduced inhibitory input to these cells, we evaluated GABA-mediated inhibitory inputs from Purkinje cells by recording spontaneous inhibitory postsynaptic currents in DCN cells from LE, LEHet, and LES animals in the presence of CNQX
In the LES rat, the absence of myelin basic protein (MBP) prevents the multi-layered wrapping of the myelin sheath and resulted in either no myelin or a thin myelin sheath with a single layer
Summary
Myelin sheaths wrap around axons to create electrical insulation, increasing efficiency of AP conduction and maintenance and protection of axons from damage due to injury or disease[1,2,3]. The reduction in the temporal fidelity of AP firing and synaptic transmission caused by dys-/demyelination critically influences the synchrony of neuronal activities with sub-millisecond accuracy in the neurosensory and motor system[6,8,9]. In dys-/demyelination, the temporal synchrony of conduction along the highly myelinated Purkinje axon could be disrupted by conduction inefficiency due to myelin loss, and affect the synaptic outputs of these axons to the DCN. Previous studies in the LES rat have shown that loss of tight and condensed myelination leads to alterations in ion channel expression at nerve terminals, and a reduction in conduction velocity and synaptic transmission in the central auditory circuit[8,9,21]. We addressed that myelin deficiency in the cerebellum reduced inhibitory synaptic transmission in the Purkinje cell-DCN synapse and altered cerebellar output
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