Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington’s disease model

Giralt, Albert; Brito, Verónica; Chevy, Quentin; Simonnet, Clémence; Otsu, Yo; Cifuentes‐Diaz, Carmen; Pins, Benoit de; Coura, Renata dos Santos; Alberch, Jordi; Ginés, Sílvia; Poncer, Jean Christophe; Girault, Jean‐Antoine

doi:10.1038/ncomms15592

Cited by 97 publications

(159 citation statements)

References 70 publications

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“…In the hippocampus of Pyk2 -/mice, we previously observed decreased levels of several synaptic proteins [15]. In the striatum, neither GluN2A nor PSD-95 levels were altered in Pyk2 -/mice (Figures 1C and D).…”

Section: Pyk2 Deletion Does Not Alter Striatal Proteinsmentioning

confidence: 70%

“…Pyk2 is a Ca 2+ -dependent non-receptor tyrosine kinase highly expressed in forebrain neurons [9] where it is activated by neuronal activity and excitatory neurotransmission [10][11][12]. Pyk2 can associate with the NMDA receptor complex and has a role in synaptic plasticity [11,[13][14][15]. Ca 2+ triggers Pyk2 autophosphorylation on Tyr-402, which recruits and activates Src-family kinases (SFKs) [16,17].…”

Section: Introductionmentioning

confidence: 99%

“…The striatal-enriched protein tyrosine phosphatase (STEP) dephosphorylates Pyk2 [18]. Activated Pyk2 regulates many cellular functions [19,20] and Pyk2 is associated with several pathologies including cancer [21], inflammatory diseases [20], Huntington's [15] and Alzheimer's diseases [22][23][24][25]. Work with Pyk2 knockout mice showed that Pyk2 in the hippocampus is involved in spatial memory and regulates spine density and morphology, as well as long-term potentiation [15] and depression [26].…”

Section: Introductionmentioning

confidence: 99%

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Pyk2 in D1 receptor-expressing neurons of the nucleus accumbens modulates the acute locomotor effects of cocaine

Pins

Montalban

Vanhoutte

et al. 2019

Preprint

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The striatum is a critical brain region for locomotor response to cocaine. Although the D1 receptor-expressing neurons are centrally involved in mediating the locomotor effects of cocaine, the molecular pathways controlling this response are not fully understood. Here we studied the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase, in striatum-related functions. We discovered that cocaine injection increases Pyk2 phosphorylation in the striatum of mice in vivo. Pyk2-deficient mice displayed an altered locomotor response to acute cocaine injection. In contrast, they developed normal locomotor sensitization and cocaine-conditioned place preference. Accordingly, a cocaine-activated signaling pathway essential for these late responses, ERK phosphorylation, was not altered.Specific deletion of Pyk2 in the nucleus accumbens or in D1 neurons reproduced this phenotype, whereas deletion of Pyk2 in the dorsal striatum or in A2A receptor-expressing neurons did not. Mice lacking Pyk2 in D1-neurons also displayed lower locomotor response to the D1 receptor agonist SKF-81297 but not to an anticholinergic drug. Our results identify Pyk2 as a regulator of acute locomotor responses to psychostimulants and suggest that changes in Pyk2 expression or activation may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine action.

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Section: Pyk2 Deletion Does Not Alter Striatal Proteinsmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pyk2 in D1 receptor-expressing neurons of the nucleus accumbens modulates the acute locomotor effects of cocaine

Pins

Montalban

Vanhoutte

et al. 2019

Preprint

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“…12,13 In contrast, Pyk2 is enriched in the postsynaptic density of neurons and serves to tune synaptic plasticity and regulate neuronal differentiation and migration in the CNS. [14][15][16][17][18][19][20] Pyk2 signaling is also involved in bone remodeling and leukocyte motility. 3,21 Canonical FAK activation involves recruitment to membrane focal adhesions via interactions with paxillin, talin, and vinculin at clustered integrins.…”

Section: Introductionmentioning

confidence: 99%

Conformational dynamics of FERM-mediated autoinhibition in Pyk2 tyrosine kinase

Loving

Underbakke

2019

Preprint

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Pyk2 is a non-receptor tyrosine kinase that evolved from gene duplication of focal adhesion kinase (FAK) and subsequent functional specialization in the brain and hemopoietic cells. Pyk2 shares a domain organization with FAK, with an N-terminal regulatory FERM domain adjoining the kinase domain. FAK regulation involves integrin-mediated membrane clustering to relieve autoinhibitory interactions between FERM and kinase domains. Pyk2 regulation remains cryptic, involving Ca 2+ influx and protein scaffolding. While the mechanism of the FAK FERM domain in autoinhibition is well-established, the regulatory role of the Pyk2 FERM is ambiguous. We probed the mechanisms of FERM-mediated autoinhibition of Pyk2 using hydrogen/deuterium exchange mass spectrometry (HDX-MS) and kinase activity profiling. The results reveal FERM-kinase interfaces responsible for autoinhibition. Pyk2 autoinhibition impacts activation loop conformation. In addition, the autoinhibitory FERM-kinase interface exhibits allosteric linkage with the FERM basic patch conserved in both FAK and Pyk2.

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“…Pyk2 is a non-receptor tyrosine kinase and is very abundantly expressed in the hippocampus of postnatal rats, reaching maximal levels in adulthood [16]. We and others recently found that Pyk2 plays important roles in dendritic and spine morphogenesis [7,17,18]. Pyk2 is post-synaptic located and interacts with NMDA receptors [19] or PSD95 [20], implicating a role of Pyk2 in both LTP [21,22] and LTD [23].…”

Section: Introductionmentioning

confidence: 99%

Pyk2 suppresses contextual fear memory in a kinase-independent manner

Zheng

Zhou

et al. 2017

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17Post-traumatic stress disorder (PTSD) is a psychological illness characterized by 18 recalling a feeling of distress when re-experiencing the original trauma-related 19 cues. This associative fear response plays an important role in some psychiatric 20 disorders and elucidation of the underlying mechanisms is of great importance. 21Here, we constructed Pyk2 null mice and found that these mutant mice showed 22 enhancement in contextual-fear memory, but no changes in auditory-cued and 23 spatial-referenced learning and memory. Moreover, using kinase mutant mice, we 24 observed that Pyk2 suppressed contextual fear memory in a kinase-independent 25 pathway. Using high-throughput RNA sequencing, we found that immediate early 26 genes (IEGs), such as Npas4, cFos, Zif268/Egr1, Arc, and Nr4a1, were enhanced 27 in Pyk2 null mice. We further demonstrated that Pyk2 disruption affected pyramidal 28 neuronal complexity and spine dynamics. Thus, we demonstrated that Pyk2 is a 29 novel fear memory suppressor molecule and Pyk2 null mice provides a model for 30understanding fear-related disorders. 31 32 between the same sets of clustered Pcdh proteins may lead to repulsion, thus self-56 avoidance and even spacing, between neurites from same neurons through 57 cytoskeletal rearrangement [14,15]. The mechanisms underlying the adhesive 58 recognition-lead repulsion is not known but may involve signaling molecules such 59 as cell-adhesion kinases. 60Pyk2 is a non-receptor tyrosine kinase and is very abundantly expressed in the 61 hippocampus of postnatal rats, reaching maximal levels in adulthood [16]. We and 62 others recently found that Pyk2 plays important roles in dendritic and spine 63 morphogenesis [7,17,18]. Pyk2 is post-synaptic located and interacts with NMDA 64 receptors [19] or PSD95 [20], implicating a role of Pyk2 in both LTP [21,22] and 65 LTD [23]. Recently, Pyk2 was also identified as a susceptibility locus for Alzheimer 66 diseases and dementias based on genome-wide association studies [24,25]. Here, 67we found Pyk2 as a repressor of contextual fear memory based on behavior 68 studies using gene modified mice by CRISPR. 69 403We thank Wuming Wang for the initial work on the project, Prof. Weidong Li (SJTU) 404 for allowing us to use his fear-conditioning testing equipment, Dr. Wenjie Bian (ION) 405 for advice on the Golgi staining, and Prof. Aaron Hsueh (Stanford) for linguistic 406 help on the manuscript. 407 408 Author Contributions 409 Mice generation: LS YXZ. 410 Study design: LS JZ YXZ QW. 411 Primary culture and biochemistry experiment: LS YXZ. 412 Animal behavior tests: LS JZ LLJ. 413 Golgi staining and picture collection: LS JZ. 414 Data analyses: LS YXZ JZ. 415 Study supervision: YPK QW. 416

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Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington’s disease model

Cited by 97 publications

References 70 publications

Pyk2 in D1 receptor-expressing neurons of the nucleus accumbens modulates the acute locomotor effects of cocaine

Pyk2 in D1 receptor-expressing neurons of the nucleus accumbens modulates the acute locomotor effects of cocaine

Conformational dynamics of FERM-mediated autoinhibition in Pyk2 tyrosine kinase

Pyk2 suppresses contextual fear memory in a kinase-independent manner

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