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

Abstract

Cerebellar learning is canonically 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 is associated with an increase in neuronal excitability. In the hippocampus, SK-mediated intrinsic plasticity has been shown to play a role in trace eyeblink conditioning; however, it is not yet known how intrinsic plasticity contributes to a cerebellar learning task such as delay eyeblink conditioning. Whole cell recordings were obtained from acute cerebellar slices from mice ~48 hours after learning a delay eyeblink conditioning task. Over a period of repeated training sessions mice received either distinctly paired trials of a tone co-terminating with a periorbital shock (conditioned mice) or trials in which these stimuli were presented in an unpaired manner (pseudoconditioned mice). Conditioned mice show a significantly reduced afterhyperpolarization (AHP) following trains of parallel fiber stimuli.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.

Complex spike clusters and false‐positive rejection in a cerebellar supervised learning rule

“…It should also be noted that single CF firing events may still lead to transient decreases in Purkinje cell simple spike firing output, thereby leading to a transient adaptive response. CS doublets have also been reported in other studies both after air puff unconditioned stimuli (Van der Giessen et al 2008) or in response to conditioned stimuli after eyeblink conditioning (Ten Brinke et al 2019). The occurrence rate of doublets varies greatly under these conditions and probably depends on the exact cerebellar region of recording, the nature of the stimuli used, and the attentional state of the animal and its expectance of incoming stimuli.…”

“…Sensory stimulation is known to increase the frequency of CS firing (Ebner & Bloedel, 1981;Bosman et al 2010;Najafi et al 2014a;Najafi et al 2014b). Enhanced CS responses have been seen after forepaw stimulation (Bloedel & Ebner, 1984), whisker stimulation (Bosman et al 2010) and corneal airpuff (Van der Giessen et al 2008), potentially driven in part by subthreshold rhythmicity of inferior olive neurons (Van der Giessen et al 2008). We examined Purkinje cell responses in mice upon repeated presentations of strong whisker stimulation ipsilateral to the recording site.…”

“…The details of mismatch at longer intervals could be explained by the involvement of multiple plasticity mechanisms in learning, some of which are triggered at longer time intervals. Indeed, it has been suggested that cerebellar motor learning rests on multiple mechanisms at multiple brain sites (Hansel et al 2001;Freeman & Steinmetz, 2011;Gao et al 2012;Titley et al 2017;Titley et al 2018).…”

SK2 channels in cerebellar Purkinje cells contribute to excitability modulation in motor-learning–specific memory traces

“…The association of learning with changes in the membrane excitability of neurons was first described in invertebrate mollusks such as Hermissenda and Aplysia [1][2][3][4][5] but is similarly found in the vertebrate hippocampus [6][7][8] and in the cerebellar cortex and nuclei [9][10][11][12]. Is there a "memory from the dynamics of intrinsic membrane currents," as previously suggested by Eve Marder and colleagues [13]?…”

Modification of Synaptic-Input Clustering by Intrinsic Excitability Plasticity on Cerebellar Purkinje Cell Dendrites

“…Therefore, the IP and branch excitability are suggested involved in the motor performance. Interestingly, an ex vivo PCs from animals experienced delay eye blink conditioning showed the reduction of after-hyperpolarization and occlusion of the IP-induction, even after 48 h later of the learning paradigm (Titley et al, 2018), suggesting the conditioned memory had been maintained not only in the cerebellar nuclei (Wang et al, 2018), but also in cerebellar cortex as the modulated excitability engram. Another study suggests lower excitability in the zebrin/aldolase C-positive PCs, through TRPC3 channels, which produces different subgroups among the cerebellar PCs (Zhou et al, 2014).…”