TheN-Methyl d-Aspartate Glutamate Receptor Antagonist Ketamine Disrupts the Functional State of the Corticothalamic Pathway

Abstract

The non-competitive N-methyl d-aspartate glutamate receptor (NMDAR) antagonist ketamine elicits a brain state resembling high-risk states for developing psychosis and early stages of schizophrenia characterized by sensory and cognitive deficits and aberrant ongoing gamma (30-80 Hz) oscillations in cortical and subcortical structures, including the thalamus. The underlying mechanisms are unknown. The goal of the present study was to determine whether a ketamine-induced psychotic-relevant state disturbs the functional state of the corticothalamic (CT) pathway. Multisite field recordings were performed in the somatosensory CT system of the sedated rat. Baseline activity was challenged by activation of vibrissa-related prethalamic inputs. The sensory-evoked thalamic response was characterized by a short-latency (∼4 ms) prethalamic-mediated negative sharp potential and a longer latency (∼10 ms) CT-mediated negative potential. Following a single subcutaneous injection of ketamine (2.5 mg/kg), spontaneously occurring and sensory-evoked thalamic gamma oscillations increased and decreased in power, respectively. The power of the sensory-related gamma oscillations was positively correlated with both the amplitude and the area under the curve of the corresponding CT potential but not with the prethalamic potential. The present results show that the layer VI CT pathway significantly contributes in thalamic gamma oscillations, and they support the hypothesis that reduced NMDAR activation disturbs the functional state of CT and corticocortical networks.

A Neurophysiological Perspective on a Preventive Treatment against Schizophrenia Using Transcranial Electric Stimulation of the Corticothalamic Pathway

“…It was demonstrated that, during rodent neural development, thalamic GFO play a crucial role in the mapping of the functional TC modules [292]. Both in humans and rodents, GFO are simultaneously present in cortex and thalamus [59,293]. In the following, we will see that GFO are also potential bioelectrical markers of psychosis, which could be used for the development of therapeutic interventions.…”

“…Importantly, the corresponding NMDAR-related response is antagonized by the NMDAR antagonist ketamine or MK-801 [207], which significantly increases the power, and the synchrony, of ongoing GFO in the highly-distributed CT-TC systems [59,60,61,62]. Moreover, the CT pathway significantly contributes to thalamic GFO [59,208]. The layer VI CT pathway also exerts a great influence on the state of the membrane potential of the TC neurons, as well as on ongoing and function-related thalamic activities.…”

“…Indeed, the membrane of the GABAergic TRN neurons can generate intrinsic subthreshold and threshold GFO, which result in rhythmic GABA(A) receptor-mediated inhibitory postsynaptic potentials in related TC neurons [232]. The oscillating properties of TRN and TC neurons are influenced by the CT pathway [59,205,208,233,234]. Therefore, the TRN plays a key role in the state-dependent generation of thalamic GFO, which are under the powerful control of large populations of layer VI CT neurons.…”

“…It is tempting to speculate that the functional dysconnectivity recorded in schizophrenia also involves a reduction of NMDAR activity. This hypothesis is supported by the fact that, in rodents, the NMDAR antagonist ketamine, at a psychotomimetic dose, disrupts the functional state of the CT pathway [59]. …”

“…Spontaneously-occurring gamma frequency (30–80 Hz) oscillations (GFO) of cortical origin, naturally implicated in attention and integration processes, are excessively amplified not only during hallucinations [50,51,52,53] but also in first-episode psychosis and in at-risk mental states for psychosis [54,55,56,57]. Such abnormally amplified GFO can be reproduced after a single systemic administration, at a psychotomimetic dose, of the glutamate N - methyl - d -aspartate receptor (NMDAR) antagonist ketamine in the corticothalamic (CT) systems of healthy humans [58] and rodents [59,60,61,62]. These translational models of first-episode psychosis highlight one important factor, glutamate synaptic transmission, which may be altered in individuals at high risk of developing psychotic disorders [63].…”