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Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M1 PAM VU6004256.

  • Grannan, Michael D1, 2
  • Mielnik, Catharine A3
  • Moran, Sean P1, 2
  • Gould, Robert W1, 2
  • Ball, Jacob1, 2
  • Lu, Zhuoyan1, 2
  • Bubser, Michael1, 2
  • Ramsey, Amy J3
  • Abe, Masahito1, 2
  • Cho, Hyekyung P1, 2
  • Nance, Kellie D2, 4
  • Blobaum, Anna L1, 2
  • Niswender, Colleen M1, 2, 5
  • Conn, P Jeffrey1, 2, 5
  • Lindsley, Craig W1, 2, 4
  • Jones, Carrie K1, 2
  • 1 Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States. , (United States)
  • 2 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States. , (United States)
  • 3 Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada. , (Canada)
  • 4 Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States. , (United States)
  • 5 Vanderbilt Kennedy Center , Nashville, Tennessee 37232, United States. , (United States)
Published Article
ACS Chemical Neuroscience
American Chemical Society
Publication Date
Dec 21, 2016
DOI: 10.1021/acschemneuro.6b00230
PMID: 27617634


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 M1 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 M1 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 M1 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 M1 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 M1 PAMs as a novel therapeutic approach for the PFC-mediated impairments in schizophrenia.

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