Cdk5/p35 is required for motor coordination and cerebellar plasticity

He, Xiaojuan; Ishizeki, Masato; Mita, Naoki; Wada, Seitaro; Araki, Yoshimori; Ogura, Hiroo; Abe, Manabu; Yamazaki, Maya; Sakimura, Kenji; Mikoshiba, Katsuhiko; Inoue, Takafumi; Ohshima, Toshio

doi:10.1111/jnc.12756

Cited by 19 publications

(24 citation statements)

References 76 publications

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“…Moreover, a long-term potentiation (LTP) induction protocol evoked significantly reduced potentiation in L7-p35 cKO PCs. These results indicate that p35 is involved in both LTD and LTP at the PF-PC synapse (He et al 2014). In summary, He et al (2014) demonstrated that Cdk5/p35 activity in PCs is required for proper motor coordination and for the formation of two forms of long-term synaptic plasticity of the cerebellum, LTD and LTP.…”

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confidence: 94%

“…In this issue, He et al (2014), provide new insights into the role of Cdk5/p35 in motor coordination and cerebellar plasticity. The authors' initial investigations of previously developed p35 deficient (p35 À/À ) transgenic mice identified impaired ability to maintain balance without noticeable muscle weakness (He et al 2014).…”

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confidence: 99%

“…The authors' initial investigations of previously developed p35 deficient (p35 À/À ) transgenic mice identified impaired ability to maintain balance without noticeable muscle weakness (He et al 2014). However, these changes in motor coordination were difficult to interpret because of abnormalities in the laminar structure of the cerebellar cortex, which included the misalignment of Purkinje cells, sparse dendritic trees of Purkinje cells and the presence of granule cells in the molecular cell layer.…”

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confidence: 99%

“…While the molecular mechanisms underlying the post-synaptic involvement of Cdk5/p35 at PF-PC synapses remains to be determined, recent studies provide important clues on how this kinase may modulate the efficacy of synaptic transmission. For example, Cdk5/p35 may modulate the ionotropic glutamate receptor (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor and N-methyl-D-aspartate receptor) content of the PSD via the regulation of striatal-enriched tyrosine phosphatase, Ca 2+ /calmodulindependent protein kinase II, PSD-95 or direct phosphorylation of the GluN2A N-methyl-D-aspartate receptor subunit (Lai and Ip 2009;Barnett and Bibb 2011;Cheung and Ip 2012;He et al 2014;Fig. 1b /calmodulin-dependent protein kinase; Cdk5, cyclin-dependent kinase 5; Glu, glutamate; IP3R1, inositol 1,4,5-trisphosphate receptor type 1; NMDAR, N-methyl-D-aspartate-type ionotropic glutamate receptor; p35, neuron-specific activator subunit of Cdk5; PSD, post-synaptic density; PSD-95, post-synaptic density protein 95; STEP, striatalenriched tyrosine phosphatize; VDCC, voltage-dependent Ca 2+ channel (based on He et al 2014).…”

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confidence: 99%

“…channels (VDCCs), L-type VDCCs and/or inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) (He et al 2014;Fig. 1b).…”

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confidence: 99%

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Motor learning and long‐term plasticity of parallel fibre‐Purkinje cell synapses require post‐synaptic Cdk5/p35

Molnár

2014

Journal of Neurochemistry

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Read the full article 'Cdk5/p35 is required for motor coordination and cerebellar plasticity' on page 53.The cerebellum plays an integral role in learning motor skills. The cerebellar cortex forms an array of relatively simple neuronal networks where Purkinje cells (PCs) receive excitatory inputs from parallel fibre (PF) varicosities, as well as from climbing fibres (CFs). PC axons provide the single output system to the deep cerebellar nuclei (Fig. 1a). The PF input of granule cells is derived by the stimulation of mossy fibres (MFs), which originate from a variety of brainstem nuclei and the spinal cord (Nakanishi 2005). The CF input arises from the inferior olivary nuclei. The role of PCs in motor learning is clearly established (Ito 2001;Gao et al. 2012). Long-term depression (LTD) at the PF-PC synapse has been proposed to be the dominant type of plasticity for cerebellar learning (Ito 2001). However, recent studies suggested that various forms of synaptic plasticity work synergistically and can compensate each other when one is missing in cerebellar learning (Gao et al. 2012). Despite growing controversies over the role of cerebellar LTD in motor learning, a recent study found that the decrease in alphaamino-3-hydroxy-5-methylisoxazole-4-propionate receptors in PF-PC synapses and elimination of these synapses are in vivo engrams in short-and long-term motor learning, respectively (Wang et al. 2014), which seems to be consistent with the LTD hypothesis (Ito 2001). These previous studies indicate that an extensive capacity of the cerebellar cortex with dynamic reorganization of PF-PC synaptic connections is fundamentally important for the learning of motor skills (Wang et al. 2014). In spite of this, the molecular mechanisms that regulate the structural and functional reorganization of PF-PC synapses are not clear.Synaptic plasticity-related changes in the structure and molecular composition of post-synaptic density (PSD) depends in part on the complex regulation of phosphorylation of specific proteins via different protein kinases, including the serine/threonine kinase, cycline-dependent kinase 5 (Cdk5) (Lai and Ip 2009). Cdk5 is activated upon association with its specific activating subunits, p35 or p39. Cdk5 is predominantly neural-specific kinase because of the restricted expression of p35 and p39 in the nervous system. The crucial roles of Cdk5 in neuronal migration, neuronal survival, differentiation, synapse development and synaptic plasticity in mature neurons are widely recognized (Lai and Ip 2009). Furthermore, dysregulation of Cdk5 has been linked to an array of neurodegenerative disorders (Lopes and Agostinho 2011;Cheung and Ip 2012). Considering the multifaceted role of Cdk5, it is not surprising that Cdk5 deficient mice exhibit perinatal lethality and defective positioning of several types of neurons (Kumazawa et al. 2013). In contrast, p35 deficient mice show a milder phenotype of positioning defects of neurons and survive to adulthood because of redundant and overlapping expression of p39 (Ku...

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confidence: 94%

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…channels (VDCCs), L-type VDCCs and/or inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) (He et al 2014;Fig. 1b).…”

mentioning

confidence: 99%

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Motor learning and long‐term plasticity of parallel fibre‐Purkinje cell synapses require post‐synaptic Cdk5/p35

Molnár

2014

Journal of Neurochemistry

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Cdk5 is required for the positioning and survival of GABAergic neurons in developing mouse striatum

Sasamoto

Nagai

Nakabayashi

et al. 2016

Developmental Neurobiology

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Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase, and its activity is dependent upon an association with a neuron-specific activating subunit. It was previously reported that Cdk5 mice exhibit perinatal lethality and defective neuronal positioning. In this study, they focused on the analysis of neuronal positioning of GABAergic neurons in the forebrain. Defective formation of the ventral striatum, nucleus accumbens, and olfactory tubercles was found in Cdk5 embryos. To further study this abnormal development, we generated and analyzed Dlx5/6-Cre p35 conditional KO (cKO); p39 mice in which forebrain GABAergic neurons have lost their Cdk5 kinase activity. Defective formation of the nucleus accumbens and olfactory tubercles as well as neuronal loss in the striatum of Dlx5/6-Cre p35cKO; p39 mice was found. Elevated levels of phosphorylated JNK were observed in neonatal striatal samples from Dlx5/6-Cre p35cKO; p39 mice, suggestive of neuronal death. These results indicate that Cdk5 is required for the formation of the ventral striatum in a cell-autonomous manner, and loss of the kinase activity of Cdk5 causes GABAergic neuronal death in the developing mouse forebrain. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017.

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Cdk5 activity is required for Purkinje cell dendritic growth in cell‐autonomous and non‐cell‐autonomous manners

Kumazawa

Kobayashi

et al. 2017

Developmental Neurobiology

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Cyclin-dependent kinase 5 (Cdk5) is recognized as a unique member among other Cdks due to its versatile roles in many biochemical processes in the nervous system. The proper development of neuronal dendrites is required for the formation of complex neural networks providing the physiological basis of various neuronal functions. We previously reported that sparse dendrites were observed on cultured Cdk5-null Purkinje cells and Purkinje cells in Wnt1 -mediated Cdk5 conditional knockout (KO) mice. In the present study, we generated L7 -mediated p35; p39 double KO (L7 -p35 ; p39 ) mice whose Cdk5 activity was eliminated specifically in Purkinje cells of the developing cerebellum. Consequently, these mice exhibited defective Purkinje cell migration, motor coordination deficiency and a Purkinje dendritic abnormality similar to what we have observed before, suggesting that dendritic growth of Purkinje cells was cell-autonomous in vivo. We found that mixed and overlay cultures of WT cerebellar cells rescued the dendritic deficits in Cdk5-null Purkinje cells, however, indicating that Purkinje cell dendritic development was also supported by non-cell-autonomous factors. We then again rescued these abnormalities in vitro by applying exogenous brain-derived neurotrophic factor (BDNF). Based on the results from culture experiments, we attempted to rescue the developmental defects of Purkinje cells in L7 -p35 ; p39 mice by using a TrkB agonist. We observed partial rescue of morphological defects of dendritic structures of Purkinje cells. These results suggest that Cdk5 activity is required for Purkinje cell dendritic growth in cell-autonomous and non-cell-autonomous manners. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1175-1187, 2017.

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Cdk5/p35 is required for motor coordination and cerebellar plasticity

Cited by 19 publications

References 76 publications

Motor learning and long‐term plasticity of parallel fibre‐Purkinje cell synapses require post‐synaptic Cdk5/p35

Motor learning and long‐term plasticity of parallel fibre‐Purkinje cell synapses require post‐synaptic Cdk5/p35

Cdk5 is required for the positioning and survival of GABAergic neurons in developing mouse striatum

Cdk5 activity is required for Purkinje cell dendritic growth in cell‐autonomous and non‐cell‐autonomous manners

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