Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M1PAM VU6004256.
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 M1muscarinic 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 M1receptor 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 M1PAM, 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 M1by 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 M1PAMs as a novel therapeutic approach for the PFC-mediated impairments in schizophrenia.
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Michael D
MD
Grannan
Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
Catharine A
CA
Mielnik
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Sean P
SP
Moran
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Robert W
RW
Gould
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Jacob
J
Ball
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Zhuoyan
Z
Lu
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Michael
M
Bubser
Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
Amy J
AJ
Ramsey
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Masahito
M
Abe
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Hyekyung P
HP
Cho
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
Kellie D
KD
Nance
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Anna L
AL
Blobaum
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Kennedy Center , Nashville, Tennessee 37232, United States.
Colleen M
CM
Niswender
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Kennedy Center , Nashville, Tennessee 37232, United States.
P Jeffrey
PJ
Conn
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
Craig W
CW
Lindsley
Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Carrie K
CK
Jones
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D018678:Cholinergic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005239:Fear / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006576:Heterocyclic Compounds, 4 or More Rings / Q000493:pharmacokinetics / Q000494:pharmacology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D018697:Nootropic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency* / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
D018678:Cholinergic Agents; C121673:Gprin1 protein, mouse; D006576:Heterocyclic Compounds, 4 or More Rings; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D016194:Receptors, N-Methyl-D-Aspartate; C000624133:VU6004256
M1 muscarinic; NR1 KD; VU6004256; antipsychotic; cognitive enhancement; positive allosteric modulator