Inhibition of NMDARs in the nucleus reticularis of the thalamus produces delta frequency bursting

Abstract

Injection of NMDAR antagonist into the thalamus can produce delta frequency EEG oscillations in the thalamocortical system. It is surprising that an antagonist of an excitatory neurotransmitter should trigger such activity, and the mechanism is unknown. One hypothesis is that the antagonist blocks excitation of GABAergic cells, thus producing disinhibition. To test this hypothesis, we investigated the effect of NMDAR antagonist (APV) on cells of the nucleus reticularis (nRT) in rat brain slices, a thalamic nucleus that can serve as a pacemaker for thalamocortical delta oscillations and that is composed entirely of GABAergic neurons. We found, unexpectedly, that nRT cells are hyperpolarized by APV. This occurs because these cells have an unusual form of NMDAR (probably NR2C) that contributes inward current at resting potential in response to ambient glutamate. The hyperpolarization produced by APV is sufficient to deinactivate T-type calcium channels, and these trigger rhythmic bursting at delta frequency. The APV-induced delta frequency bursting is abolished by dopamine D2 receptor antagonist, indicating that dopamine and NMDAR antagonist work synergistically to stimulate delta frequency bursting. Our results have significant implications concerning the electrophysiological basis of schizophrenia and bring together the NMDAR hypofunction, dopamine, and GABA theories of the disease. Our results suggest that NMDAR hypofunction and dopamine work synergistically on the GABAergic cells of the nRT to generate the delta frequency EEG oscillations, a thalamocortical dysrhythmia (TCD) in the awake state that is an established abnormality in schizophrenia.

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

“…In contrast to the PFC, we found that the bipartite functional connectivity of the thalamus to the neuromodulatory subsystem and HP was decreased, whereas thalamic connectivity to the cortical subsystems was increased by acute ketamine treatment. The direct inhibition of thalamic GABAergic neurons, consistent with the decreased metabolic demand of these nuclei (Figure 1, as 2-DG imaging largely reflects the metabolic demands of localized synapses), by NMDA receptor blockade (Zhang et al, 2009) may underlie the functional dysconnectivity of this neural subsystem from that of the neuromodulatory nuclei. In addition this would lead to the disinhibition of thalamic glutamatergic projections to the cortex and other neural subsystems (Sharp et al, 2001), a suggestion consistent with the enhanced bipartite thalamus-cortex connectivity also seen in ketamine-treated animals.…”

“…Interestingly, we did find evidence for enhanced thalamic connectivity to cortical regions (Figure 4c), with the exception of the PFC, following ketamine treatment in this study. Our previous data, and data from other groups, suggest that the direct actions of ketamine in the reticular thalamus (RT) may be a key mechanism through which ketamine promotes the abnormal connectivity of other thalamic regions, in part through the disinhibition of thalamocortical projections (Dawson et al, 2013;Zhang et al, 2009). Given that the cognitive and functional roles of specific thalamic nuclei and their cortical connections are poorly defined, with the exception of the PFC-thalamic connection, the potential contribution of these alterations to ketamine's ability to model schizophrenia certainly warrants further systematic investigation.…”

GluN2D N-Methyl-D-Aspartate Receptor Subunit Contribution to the Stimulation of Brain Activity and Gamma Oscillations by Ketamine: Implications for Schizophrenia

“…Thus, GluN2D subunits contribute to excitatory disinhibition, an important subset of ketamine's actions, but not to other effects of ketamine. The ketamine-induced reduction in 2DG uptake in somatosensory cortex that persists in the GluN2D-KO potentially reflects the ketamine blockade of GluN2C-containing receptors in thalamic reticular nucleus interneurons, which would promote delta/theta oscillations and reduced activity in somatosensory cortex via the specific thalamocortical projections (Llinas et al, 2005;Zhang et al, 2009).…”

Altered thalamocortical rhythmicity and connectivity in mice lacking Ca V 3.1 T-type Ca 2+ channels in unconsciousness

“…It is well known that hyperpolarization, generated by NMDA receptor block, is sufficient to deinactivate T-type Ca 2+ channels, resulting in rhythmic thalamic bursting (20). By contrast, ethanol, known to elicit thalamic extrasynaptic GABA A -mediated tonic inhibition, also results in their burst firing via membrane hyperpolarization (21).…”