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J Neurosci. 2020 Jan 31. pii: 2259-19. doi: 10.1523/JNEUROSCI.2259-19.2019. [Epub ahead of print]

Intrinsic Excitability Increase in Cerebellar Purkinje Cells Following Delay Eyeblink Conditioning in Mice.

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Department of Neurobiology, University of Chicago, Chicago, IL, 60637.
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611.
Department of Neurobiology, University of Chicago, Chicago, IL, 60637


Cerebellar-based learning is thought to rely on synaptic plasticity, particularly at synaptic inputs to Purkinje cells. Recently, however, other complementary mechanisms have been identified. Intrinsic plasticity is one such mechanism, and depends in part on the down-regulation of calcium-dependent SK-type K+ channels, which contribute to a medium-slow afterhyperpolarization (AHP) following spike bursts, regulating membrane excitability. In the hippocampus, intrinsic plasticity plays a role in trace eyeblink conditioning; however, corresponding excitability changes in the cerebellum in associative learning, such as in trace or delay eyeblink conditioning, are less well studied. Whole-cell patch-clamp recordings were obtained from Purkinje cells in cerebellar slices prepared from male mice ∼48 hours after learning a delay eyeblink conditioning task. Over a period of repeated training sessions mice received either paired trials of a tone co-terminating with a periorbital shock (conditioning) or trials in which these stimuli were randomly presented in an unpaired manner (pseudoconditioning). Purkinje cells from conditioned mice show a significantly reduced AHP following trains of parallel fiber stimuli and following climbing fiber evoked complex spikes. The number of spikelets in the complex spike waveform is enhanced after conditioning. Moreover, we find that SK-dependent intrinsic plasticity is occluded in conditioned, but not pseudoconditioned mice. These findings show that excitability is enhanced in Purkinje cells after delay eyeblink conditioning, and point toward a downregulation of SK channels as a potential underlying mechanism. The observation that this learning effect lasts at least up to two days following training shows that intrinsic plasticity regulates excitability in the long-term.SIGNIFICANCE STATEMENTPlasticity of membrane excitability ('intrinsic plasticity') has been observed in invertebrate and vertebrate neurons, co-induced with synaptic plasticity or in isolation. While the cellular phenomenon per se is well-established, it remains unclear what role intrinsic plasticity plays in learning, and whether it even persists long enough to serve functions in engram physiology beyond aiding synaptic plasticity. Here, we demonstrate that cerebellar Purkinje cells upregulate excitability in delay eyeblink conditioning, a form of motor learning. This plasticity is observed 48 hours after training, and alters synaptically-evoked spike firing and integrative properties of these neurons. These findings show that intrinsic plasticity enhances the spike firing output of Purkinje cells, and persists over the course of days.

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