Altered physiology of Purkinje neurons in cerebellar slices from transgenic mice with chronic central nervous system expression of interleukin-6.
The cytokine interleukin-6 is produced at elevated levels within the central nervous system in a number of neurological diseases and has been proposed to contribute to the histopathologic, pathophysiologic, and cognitive deficits associated with such disorders. In order to determine the effects of chronic exposure of interleukin-6 on the physiology of central neurons, we compared the firing properties of cerebellar Purkinje neurons from control mice and transgenic mice that chronically express interleukin-6 within the central nervous system. Extracellular recordings from cerebellar slices revealed that the mean firing rate of spontaneously active Purkinje neurons was significantly reduced in slices from transgenic mice compared to control mice. In addition, a significantly greater proportion of Purkinje neurons from transgenic slices exhibited an oscillatory pattern of spontaneous firing than neurons in control slices. Orthodromic stimulation of climbing fiber afferents evoked similar excitatory synaptic responses (complex spikes) in Purkinje neurons of both transgenic and control mice. However, the inhibitory period following the complex spike (climbing fiber pause) was significantly longer in slices from transgenic mice. Using immunohistochemistry, we also showed that Purkinje neurons express high levels of both the interleukin-6 receptor and its intracellular signaling subunit, gp130, indicating that interleukin-6 could act directly on Purkinje neurons to alter their physiological properties. The interleukin-6 expressing transgenic mice have been shown previously to exhibit a number of histopathological changes in the central nervous system including injury and loss of cerebellar Purkinje neurons. The present data show that these transgenic mice also have altered physiology of cerebellar Purkinje neurons, potentially through a direct activation of interleukin-6 receptors expressed by this neuronal type. Interleukin-6 induced alterations of Purkinje neuron physiology would ultimately affect the flow of information out of the cerebellum, and could thus contribute to the motor deficits observed in the transgenic mice.
Nelson
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Department of Neuropharmacology and AIDS Research Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Campbell
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Gruol
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D000367:Age Factors; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001923:Brain Chemistry / Q000235:genetics*; D050822:Cytokine Receptor gp130; D004594:Electrophysiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D015850:Interleukin-6 / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D011689:Purkinje Cells / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
D015703:Antigens, CD; D005904:Glial Fibrillary Acidic Protein; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D050822:Cytokine Receptor gp130