PMID- 27617634
OWN - NLM
STAT- MEDLINE
DCOM- 20171020
LR  - 20191210
IS  - 1948-7193 (Electronic)
IS  - 1948-7193 (Linking)
VI  - 7
IP  - 12
DP  - 2016 Dec 21
TI  - Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor 
      Hypofunction Are Reversed by the Novel M(1) PAM VU6004256.
PG  - 1706-1716
LID - 10.1021/acschemneuro.6b00230 [doi]
AB  - Abnormalities in the signaling of the N-methyl-d-aspartate subtype of the 
      glutamate receptor (NMDAR) within cortical and limbic brain regions are thought 
      to underlie many of the complex cognitive and affective symptoms observed in 
      individuals with schizophrenia. The M(1) muscarinic acetylcholine receptor 
      (mAChR) subtype is a closely coupled signaling partner of the NMDAR. Accumulating 
      evidence suggests that development of selective positive allosteric modulators 
      (PAMs) of the M(1) receptor represent an important treatment strategy for the 
      potential normalization of disruptions in NMDAR signaling in patients with 
      schizophrenia. In the present studies, we evaluated the effects of the novel and 
      highly potent M(1) PAM, VU6004256, in ameliorating selective prefrontal cortical 
      (PFC)-mediated physiologic and cognitive abnormalities in a genetic mouse model 
      of global reduction in the NR1 subunit of the NMDAR (NR1 knockdown [KD]). Using 
      slice-based extracellular field potential recordings, deficits in muscarinic 
      agonist-induced long-term depression (LTD) in layer V of the PFC in the NR1 KD 
      mice were normalized with bath application of VU6004256. Systemic administration 
      of VU6004256 also reduced excessive pyramidal neuron firing in layer V PFC 
      neurons in awake, freely moving NR1 KD mice. Moreover, selective potentiation of 
      M(1) by VU6004256 reversed the performance impairments of NR1 KD mice observed in 
      two preclinical models of PFC-mediated learning, specifically the novel object 
      recognition and cue-mediated fear conditioning tasks. VU6004256 also produced a 
      robust, dose-dependent reduction in the hyperlocomotor activity of NR1 KD mice. 
      Taken together, the current findings provide further support for M(1) PAMs as a 
      novel therapeutic approach for the PFC-mediated impairments in schizophrenia.
FAU - Grannan, Michael D
AU  - Grannan MD
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
FAU - Mielnik, Catharine A
AU  - Mielnik CA
AD  - Department of Pharmacology and Toxicology, University of Toronto , Toronto, 
      Ontario M5S 1A8, Canada.
FAU - Moran, Sean P
AU  - Moran SP
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
FAU - Gould, Robert W
AU  - Gould RW
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
FAU - Ball, Jacob
AU  - Ball J
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
FAU - Lu, Zhuoyan
AU  - Lu Z
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
FAU - Bubser, Michael
AU  - Bubser M
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
FAU - Ramsey, Amy J
AU  - Ramsey AJ
AD  - Department of Pharmacology and Toxicology, University of Toronto , Toronto, 
      Ontario M5S 1A8, Canada.
FAU - Abe, Masahito
AU  - Abe M
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
FAU - Cho, Hyekyung P
AU  - Cho HP
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
FAU - Nance, Kellie D
AU  - Nance KD
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
AD  - Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, 
      United States.
FAU - Blobaum, Anna L
AU  - Blobaum AL
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
FAU - Niswender, Colleen M
AU  - Niswender CM
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
AD  - Vanderbilt Kennedy Center , Nashville, Tennessee 37232, United States.
FAU - Conn, P Jeffrey
AU  - Conn PJ
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
AD  - Vanderbilt Kennedy Center , Nashville, Tennessee 37232, United States.
FAU - Lindsley, Craig W
AU  - Lindsley CW
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
AD  - Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, 
      United States.
FAU - Jones, Carrie K
AU  - Jones CK
AD  - Department of Pharmacology, Vanderbilt University Medical Center , Nashville, 
      Tennessee 37232, United States.
AD  - Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical 
      Center , Nashville, Tennessee 37232, United States.
LA  - eng
GR  - T32 MH064913/MH/NIMH NIH HHS/United States
GR  - R01 MH073676/MH/NIMH NIH HHS/United States
GR  - U54 HD083211/HD/NICHD NIH HHS/United States
GR  - R01 MH086601/MH/NIMH NIH HHS/United States
GR  - R01 MH082867/MH/NIMH NIH HHS/United States
GR  - MOP119298/CIHR/Canada
PT  - Journal Article
DEP - 20161005
PL  - United States
TA  - ACS Chem Neurosci
JT  - ACS chemical neuroscience
JID - 101525337
RN  - 0 (Cholinergic Agents)
RN  - 0 (Gprin1 protein, mouse)
RN  - 0 (Heterocyclic Compounds, 4 or More Rings)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nootropic Agents)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (VU6004256)
SB  - IM
MH  - Action Potentials/drug effects/physiology
MH  - Animals
MH  - Cholinergic Agents/pharmacokinetics/*pharmacology
MH  - Cognition Disorders/drug therapy/metabolism
MH  - Conditioning, Psychological/drug effects/physiology
MH  - Disease Models, Animal
MH  - Drug Evaluation, Preclinical
MH  - Fear/drug effects/physiology
MH  - Gene Knockdown Techniques
MH  - Heterocyclic Compounds, 4 or More Rings/pharmacokinetics/*pharmacology
MH  - Long-Term Synaptic Depression/drug effects/physiology
MH  - Male
MH  - Mice, 129 Strain
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Motor Activity/drug effects/physiology
MH  - Nerve Tissue Proteins/*deficiency/genetics
MH  - Nootropic Agents/pharmacokinetics/*pharmacology
MH  - Prefrontal Cortex/*drug effects/*metabolism
MH  - Pyramidal Cells/drug effects/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/*deficiency/genetics
MH  - Recognition, Psychology/drug effects/physiology
MH  - Tissue Culture Techniques
PMC - PMC5231396
MID - NIHMS840558
OTO - NOTNLM
OT  - M1 muscarinic
OT  - NR1 KD
OT  - VU6004256
OT  - antipsychotic
OT  - cognitive enhancement
OT  - positive allosteric modulator
COIS- The authors declare the following competing financial interest(s): Over the past 
      year, C.W.L. consulted for Abbott. M.B., T.M.B., C.W.L., P.J.C., and C.K.J. 
      received research/salary support from AstraZeneca and/or Bristol Myers Squibb. 
      C.M.N., C.W.L., and P.J.C. are inventors on multiple composition of matter 
      patents protecting allosteric modulators of GPCRs. The remaining authors declare 
      no competing financial interests.
EDAT- 2016/09/13 06:00
MHDA- 2017/10/21 06:00
PMCR- 2017/12/21
CRDT- 2016/09/13 06:00
PHST- 2016/09/13 06:00 [pubmed]
PHST- 2017/10/21 06:00 [medline]
PHST- 2016/09/13 06:00 [entrez]
PHST- 2017/12/21 00:00 [pmc-release]
AID - 10.1021/acschemneuro.6b00230 [doi]
PST - ppublish
SO  - ACS Chem Neurosci. 2016 Dec 21;7(12):1706-1716. doi: 
      10.1021/acschemneuro.6b00230. Epub 2016 Oct 5.