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September 3, 2026Biological Psychiatry Global Open ScienceOpen Access

Selective mGlu1 Receptor Activation Restores Cortical Inhibitory Tone and Improves Cognitive Performance in a Subchronic Phencyclidine NMDA Hypofunction Model

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Authors

DLDeborah J. LuessenVanderbilt UniversityIGIsabel GallingerVanderbilt UniversityBWBrenna WolfeSUNY Oneonta

Discussion

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Implication

Preclinical study reveals that selective mGlu1 receptor activation restores prefrontal inhibition and cognitive function in mice, indicating a potential therapeutic strategy for schizophrenia.

Key Points

  • To determine whether selective mGlu1 receptor activation rescues prefrontal cortical inhibitory transmission and reverses cognitive deficits in a phencyclidine-induced NMDA hypofunction model.
  • Administered subchronic phencyclidine (PCP) to mice to induce NMDA receptor hypofunction and treated them with mGlu1 positive allosteric modulators (PAMs).
  • Assessed wild-type mice alongside transgenic mice with selective deletion of mGlu1 receptors from somatostatin-expressing GABAergic interneurons.
  • Measured prefrontal cortical inhibitory transmission using ex vivo whole-cell patch-clamp electrophysiology and evaluated cognitive function with working memory and novel object recognition tasks.
  • Subchronic PCP treatment degraded inhibitory synaptic transmission onto prefrontal cortex layer V pyramidal neurons projecting to the nucleus accumbens.
  • Pharmacological mGlu1 activation restored cortical inhibitory transmission and reversed PCP-induced impairments in working memory and novel object recognition.
  • Selective deletion of mGlu1 receptors from somatostatin interneurons completely abolished the ability of mGlu1 PAMs to restore cortical inhibition and cognitive performance.

Cite This Study

Luessen et al. (2026) studied this question.

synapsesocial.com/papers/6a993586636c6408cfa7dc32https://doi.org/10.1016/j.bpsgos.2026.100819
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