NMDA Receptor Hypofunction Produces Opposite Effects on Prefrontal Cortex Interneurons and Pyramidal Neurons

By H. Homayoun, B. Moghaddam. Journal of Neuroscience, 2007

1,246 citations recorded by the source corpus.

NMDA receptors mediate excitatory postsynaptic potentials throughout the brain but, paradoxically, NMDA receptor antagonists produce cortical excitation in humans and behaving rodents. To elucidate a mechanism for these diverging effects, we examined the effect of use-dependent inhibition of NMDA receptors on the spontaneous activity of putative GABA interneurons and pyramidal neurons in the prefrontal cortex of awake rats. We find that inhibition of NMDA receptors predominately decreases the activity of putative GABA interneurons but, at a delayed rate, increases the firing rate of the majority of pyramidal neurons. Thus, NMDA receptors preferentially drive the activity of cortical inhibitory interneurons suggesting that NMDA receptor inhibition causes cortical excitation by disinhibition of pyramidal neurons. These findings support the hypothesis that NMDA receptor hypofunction, which has been implicated in the pathophysiology of schizophrenia, diminishes the inhibitory control of PFC output neurons. Reducing this effect may be critical for treatment of schizophrenia.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9a94cf47b787ad7dbf28ee9b5904d311a1907340

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Citations in the corpus

Abnormal neural oscillations and synchrony in schizophrenia (2010, background): “This paradoxical result could be due to the disinhibition of principal cells as a result of reduced interneuron excitatio”
From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment (2012, background): “The critical question in this context has been what is the mechanism by which an NMDAR antagonist increases and thus disorganizes the firing of cortical neurons? The most straightforward mechanism is the so-called cortical disinhibition process (Homayoun and Moghaddam, 2007b).”
Glutamate and dopamine in schizophrenia: an update for the 21st century (2015, background): “Specifically, NMDA receptor antagonists have been shown to reduce GABAergic interneuron function (Homayoun and Moghaddam, 2007), and it is thought that this leads to an increase in pyramidal cell firing due to disinhibition (Olney and Farber, 1995).”
Biological Psychology : Stress (2016, neutral): “(Homayoun & Moghaddam, 2007; Moghaddam & Javitt, 2012).”
The neurobiology of psychedelic drugs: implications for the treatment of mood disorders (2010, background): “These effects are probably due to a blockade of NMDA receptors on GABA (γ-aminobutyric acid)-ergic interneuron”
The development of oscillatory and aperiodic resting state activity is linked to a sensitive period in humans (2023, background): “Pharmacologically blocking NMDA receptors causes a reduction in the firing rate of fastspiking GABAergic interneurons while the firing rate of pyramidal neurons remains unchanged or increases (Homayoun and Moghaddam, 2007; Quirk, 2009).”