Long-Term Potentiation at the Mossy Fiber–Granule Cell Relay Invokes Postsynaptic Second-Messenger Regulation of Kv4 Channels

Rizwan, Arsalan P.; Zhan, Xiaoqin; Zamponi, Gerald W.; Turner, Ray W.

doi:10.1523/jneurosci.2051-16.2016

Cited by 20 publications

(33 citation statements)

References 53 publications

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“…Nav1.6 labeling appears consistent with somatic and axonal initial segment localization 35,42 , which aligns with previous reports using the same antibody 73,74 . Kv4.3 labeling is consistent with somatic localization in layer V pyramidal neurons 75 , and corresponds with validated labeling in hippocampal CA3 neurons using the vendor antibody 76 . Finally, Kv7.2 labeling appears to be expressed in axons and synaptic terminals 62,63 , where our specific antibody has been confirmed with heavy colocalization in the Nodes of Ranvier 77 .…”

Section: Discussionsupporting

confidence: 77%

Alterations in Ion Channel Expression Surrounding Implanted Microelectrode Arrays in the Brain

2019

Preprint

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Microelectrode arrays designed to map and modulate neuronal circuitry have enabled greater understanding and treatment of neurological injury and disease. Reliable detection of neuronal activity over time is critical for the successful application of chronic recording devices. Here, we assess devicerelated plasticity by exploring local changes in ion channel expression and their relationship to device performance over time. We investigated four voltage-gated ion channels (Kv1.1, Kv4.3, Kv7.2, and Nav1.6) based on their roles in regulating action potential generation, firing patterns, and synaptic efficacy. We found that a progressive increase in potassium channel expression and reduction in sodium channel expression accompanies signal loss over 6 weeks (both LFP amplitude and number of units). This motivated further investigation into a mechanistic role of ion channel expression in recorded signal instability. We employed siRNA in neuronal culture to find that Kv7.2 knockdown (as a model for the transient downregulation observed at 1 day in vivo) mimics excitatory synaptic remodeling around devices. This work provides new insight into the mechanisms underlying signal loss over time.

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Section: Discussionsupporting

confidence: 77%

Alterations in Ion Channel Expression Surrounding Implanted Microelectrode Arrays in the Brain

2019

Preprint

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“…Thus, our data show that KChIP3 and KChIP4 were expressed in the same neuronal populations as Kv4.2 and Kv4.3, and this included PCs and GCs. The present findings are in agreement with previous studies showing that the mRNA and protein for KChIP3 and KChIP4 are distributed in PCs and GCs [ 19 , 22 ], two neuron populations that also express Kv4.2 and Kv4.3 transcripts and proteins [ 22 , 23 , 28 , 29 , 30 ]. Interestingly, our single-label immunoperoxidase immunohistochemistry also showed that only KChIP3 and Kv4.3 were found in interneurons (basket and stellate cells) in the molecular layer, suggesting that some cerebellar neurons also show differential association between KChIPs and Kv4.…”

Section: Discussionsupporting

confidence: 94%

“…Because there are few published high-resolution immunoelectron microscopic and electrophysiological data showing the precise localisation of KChIP and Kv4 subunits in the cerebellum, it is difficult to draw conclusions about the functional significance of our results at present. On the basis of previous and present results, one possibility is that Kv4 and KChIP are related with LTP at the mossy fibre–granule cell, known to be regulated by Kv4 channels [ 30 ]. Given that this LTP has also been attributed to presynaptic mechanisms [ 45 ], further electrophysiological studies will be essential to unravel a specific role carried out by KChIP and Kv4 α subunits channels located at axon terminals.…”

Section: Discussionmentioning

confidence: 92%

Cellular and Subcellular Localisation of Kv4-Associated KChIP Proteins in the Rat Cerebellum

Alfaro-Ruiz

Aguado

Martín-Belmonte

et al. 2020

IJMS

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The K+ channel interacting proteins (KChIPs) are a family of cytosolic proteins that interact with Kv4 channels, leading to higher current density, modulation of channel inactivation and faster recovery from inactivation. Using immunohistochemical techniques at the light and electron microscopic level combined with quantitative analysis, we investigated the cellular and subcellular localisation of KChIP3 and KChIP4 to compare their distribution patterns with those for Kv4.2 and Kv4.3 in the cerebellar cortex. Immunohistochemistry at the light microscopic level demonstrated that KChIP3, KChIP4, Kv4.2 and Kv4.3 proteins were widely expressed in the cerebellum, with mostly overlapping patterns. Immunoelectron microscopic techniques showed that KChIP3, KChIP4, Kv4.2 and Kv4.3 shared virtually the same somato-dendritic domains of Purkinje cells and granule cells. Application of quantitative approaches showed that KChIP3 and KChIP4 were mainly membrane-associated, but also present at cytoplasmic sites close to the plasma membrane, in dendritic spines and shafts of Purkinje cells (PCs) and dendrites of granule cells (GCs). Similarly, immunoparticles for Kv4.2 and Kv4.3 were observed along the plasma membrane and at intracellular sites in the same neuron populations. In addition to the preferential postsynaptic distribution, KChIPs and Kv4 were also distributed presynaptically in parallel fibres and mossy fibres. Immunoparticles for KChIP3, KChIP4 and Kv4.3 were detected in parallel fibres, and KChIP3, KChIP4, Kv4.2 and Kv4.3 were found in parallel fibres, indicating that composition of KChIP and Kv4 seems to be input-dependent. Together, our findings unravelled previously uncharacterised KChIP and Kv4 subcellular localisation patterns in neurons, revealed that KChIP have additional Kv4-unrelated functions in the cerebellum and support the formation of macromolecular complexes between KChIP3 and KChIP4 with heterotetrameric Kv4.2/Kv4.3 channels.

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“…However, whether these neuronal networks perform a 50 Fourier-like transform on their inputs remains unknown. 51 between lobule V and IX differed (Figure 1-figure supplement 1), consistent 125 with previously described differences in, e.g., the firing frequency in vivo between 126 these two lobules (Witter and De Zeeuw, 2015a;Zhou et al, 2014) and in the 127 differential density of Kv4 and Cav3 channel expression in GCs across different 128 lobules (Heath et al, 2014;Rizwan et al, 2016;Serôdio and Rudy, 1998). Taking 129 the large functional difference between spino-and vestibulo-cerebellum into 130 account (Witter and De Zeeuw, 2015b), these data suggest that different 131 biophysical properties of GCs is likely a conserved mechanism throughout the 132 entire cerebellar cortex, potentially tuning GCs to different frequencies.…”

Section: Introduction 35supporting

confidence: 79%

Gradients in the cerebellar cortex enable Fourier-like transformation and improve storing capacity

Straub¹,

Witter

Eshra³

et al. 2019

Preprint

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20Cerebellar granule cells (GCs) making up majority of all the neurons in the 21 vertebrate brain, but heterogeneities among GCs and potential functional 22 consequences are poorly understood. Here, we identified unexpected gradients 23 in the biophysical properties of GCs. GCs closer to the white matter (inner-zone 24 GCs) had higher firing thresholds and could sustain firing with larger current 25 inputs. Dynamic clamp experiments showed that inner-and outer-zone GCs 26 preferentially respond to high-and low-frequency mossy fiber inputs, 27 respectively, enabling to disperse the mossy fiber input into its frequency 28 components as performed by a Fourier transformation. Furthermore, inner-zone 29GCs have faster axonal conduction velocity and elicit faster synaptic potentials in 30 Purkinje cells. Neuronal network modeling revealed that these gradients improve 31 spike-timing precision of Purkinje cells and decrease the number of GCs required 32 to learn spike-sequences. Thus, our study uncovers biophysical gradients in the 33 cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs. 34Controlling the timing and precision of movements is considered to be one of the 52 main functions of the cerebellum. In the cerebellum, the firing frequency of 53Purkinje cells (PCs) (Heiney et al., 2014;Herzfeld et al., 2015; Hewitt et al., 54 2011;Medina and Lisberger, 2007;Payne et al., 2019; Sarnaik and Raman, 55 2018;Witter et al., 2013) or the timing of spikes (Brown and Raman, 2018; 56 Sarnaik and Raman, 2018) have been shown to be closely related to movement. 57Indeed, cerebellar pathology impairs precision in motor learning tasks (Gibo et 58 al., 2013;Martin et al., 1996) and timing of rhythmic learning tasks (Keele and 59 Ivry, 1990). These functions are executed by a remarkably simple neuronal 60 network architecture. Inputs from mossy fibers (MFs) are processed by GCs and 61 transmitted via their parallel fiber (PF) axons to PCs, which provide the sole 62 output from the cerebellar cortex. GCs represent the first stage in cerebellar 63 processing and have been proposed to provide pattern separation and 64 3 conversion into a sparser representation of the MF input (recently reviewed by 65 (Cayco-Gajic and Silver, 2019). These MF inputs show a wide variety of signaling 66 frequencies, ranging from slow modulating activity to kilohertz bursts of activity 67 (Arenz et al., 2008;Rancz et al., 2007; Ritzau-Jost et al., 2014; van Kan et al., 68 1993). Interestingly, in cellular models of the cerebellum, each MF is considered 69 to be either active or inactive with little consideration for this wide range of 70 frequencies (Albus, 1971;Marr, 1969). Furthermore, in these models, GCs are 71 generally considered as a uniform population of neurons. 72 Here we show that the biophysical properties of GCs differ according to their 73 vertical position in the GC layer. GCs located close to the white matter (inner-74 zone) selectively transmit high-frequency MF inputs, have shorter action 75 poten...

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Long-Term Potentiation at the Mossy Fiber–Granule Cell Relay Invokes Postsynaptic Second-Messenger Regulation of Kv4 Channels

Cited by 20 publications

References 53 publications

Alterations in Ion Channel Expression Surrounding Implanted Microelectrode Arrays in the Brain

Alterations in Ion Channel Expression Surrounding Implanted Microelectrode Arrays in the Brain

Cellular and Subcellular Localisation of Kv4-Associated KChIP Proteins in the Rat Cerebellum

Gradients in the cerebellar cortex enable Fourier-like transformation and improve storing capacity

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