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Hippocampal protein kinase D1 is necessary for DHPG-induced learning and memory impairments in rats.

Title: Hippocampal protein kinase D1 is necessary for DHPG-induced learning and memory impairments in rats.
Name(s): Wang, Wei, author
Duclot, Florian, author
Groveman, Bradley R, author
Carrier, Nicole, author
Qiao, Haifa, author
Fang, Xiao-Qian, author
Wang, Hui, author
Xin, Wenkuan, author
Jiang, Xing-Hong, author
Salter, Michael W, author
Ding, Xin-Sheng, author
Kabbaj, Mohamed, author
Yu, Xian-Min, author
Type of Resource: text
Genre: Journal Article
Date Issued: 2018-04-03
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs. The knockdown of PKD1 does not affect the DHPG-induced inhibition of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) but prevents the DHPG-induced inhibition of NMDAR-mediated mEPSCs in vitro. Thus, we investigated the in vivo effects of bilateral infusions of DHPG into the hippocampal CA1 area of rats in the Morris water maze (MWM) and the novel object discrimination (NOD) tests. A total of 300 adult male Sprague Dawley rats (250-280 g) were used for behavioral tests. One hundred ninety four were used in MWM test and the other 106 rats in the NOD test. Following one week of habituation to the vivarium, rats were bilaterally implanted under deep anesthesia with cannulas aimed at the CA1 area of the hippocampus (CA1 coordinates in mm from Bregma: AP -3.14; lateral +/-2; DV -3.0). Through implanted cannulas artificial cerebrospinal fluid (ACSF), the group1 mGluR antagonist 6-Methyl-2-(phenylethynyl)pyridine (MPEP), the dynamin-dependent internalization inhibitor Dynasore, or the PKD1 inhibitor CID755673 were infused into the bilateral hippocampal CA1 areas (2 μL per side, over 5 min). The effects of these infusions and the effects of PKD1 knockdown were examined in MWM or NOD test. DHPG infusion increased the latency to reach the platform in the MWM test and reduced the preference for the novel object in the NOD task. We found that the DHPG effects were dose-dependent and could be maintained for up to 2 days. Notably, these effects could be prevented by pre-infusion of the group1 mGluR antagonist MPEP, the dynamin-dependent internalization inhibitor Dynasore, the PKD1 inhibitor CID755673, or by PKD1 knockdown in the hippocampal CA1 area. Altogether, these findings provide direct evidence that PKD1-mediated signaling may play a critical role in the induction of learning and memory impairments by DHPG infusion into the hippocampal CA1 area.
Identifier: FSU_pmch_29614089 (IID), 10.1371/journal.pone.0195095 (DOI), PMC5882104 (PMCID), 29614089 (RID), 29614089 (EID), PONE-D-17-33748 (PII)
Grant Number: R01 NS053567
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at
Subject(s): Animals
CA1 Region, Hippocampal/metabolism
CA1 Region, Hippocampal/physiopathology
Disease Models, Animal
Dose-Response Relationship, Drug
Gene Knockout Techniques
Learning Disorders/etiology
Learning Disorders/physiopathology
Maze Learning
Memory Disorders/etiology
Memory Disorders/physiopathology
Methoxyhydroxyphenylglycol/adverse effects
Methoxyhydroxyphenylglycol/analogs & derivatives
Protein Kinase C/genetics
Protein Kinase C/metabolism
Spatial Memory
Persistent Link to This Record:
Host Institution: FSU
Is Part Of: PloS one.
Issue: iss. 4, vol. 13

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Wang, W., Duclot, F., Groveman, B. R., Carrier, N., Qiao, H., Fang, X. -Q., … Yu, X. -M. (2018). Hippocampal protein kinase D1 is necessary for DHPG-induced learning and memory impairments in rats. Plos One. Retrieved from