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

Grannan MD, Mielnik CA, Moran SP, Gould RW, Ball J, Lu Z, Bubser M, Ramsey AJ, Abe M, Cho HP, Nance KD, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW, Jones CK
ACS Chem Neurosci. 2016 7 (12): 1706-1716

PMID: 27617634 · PMCID: PMC5231396 · DOI:10.1021/acschemneuro.6b00230

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

MeSH Terms (23)

Action Potentials Animals Cholinergic Agents Cognition Disorders Conditioning (Psychology) Disease Models, Animal Drug Evaluation, Preclinical Fear Gene Knockdown Techniques Heterocyclic Compounds, 4 or More Rings Long-Term Synaptic Depression Male Mice, 129 Strain Mice, Inbred C57BL Mice, Transgenic Motor Activity Nerve Tissue Proteins Nootropic Agents Prefrontal Cortex Pyramidal Cells Receptors, N-Methyl-D-Aspartate Recognition (Psychology) Tissue Culture Techniques

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