Neuronal activity patterns in the mediodorsal thalamus and related cognitive circuits are modulated by metabotropic glutamate receptors

Abstract

The mediodorsal thalamus (MD) likely plays an important role in cognition as it receives abundant afferent connections from the amygdala and prefrontal cortex (PFC). Indeed, disturbed activity within the MD is thought to precipitate cognitive deficits associated with schizophrenia. As compounds acting at the Group II metabotropic glutamate (mGlu) receptors (subtypes mGlu2/mGlu3) have efficacy in animal models of schizophrenia, we investigated whether a Group II agonist and an mGlu2 positive allosteric modulator (PAM) could modulate MD activity. Extracellular single-unit recordings were made in vivo from MD neurones in anaesthetised rats. Responses were elicited by electrical stimulation of the PFC and/or amygdala, with Group II compounds locally applied as required. The Group II agonist reduced inhibition evoked in the MD: an effect manifested as an increase in short-latency responses, and a decrease in long-latency burst-firing. This disinhibitory action of the Group II receptors in the MD represents a mechanism of potential therapeutic importance as increased inhibition in the MD has been associated with cognitive deficit-onset. Furthermore, as co-application of the mGlu2 PAM did not potentiate the Group II agonist effects in the MD, we suggest that the Group II disinhibitory effect is majority-mediated via mGlu3. This heterogeneity in Group II receptor thalamic physiology bears consequence, as compounds active exclusively at the mGlu2 subtype are unlikely to perturb maladapted MD firing patterns associated with cognitive deficits, with activity at mGlu3 receptors possibly more appropriate. Indeed, polymorphisms in the mGlu3, but not the mGlu2, gene have been detected in patients with schizophrenia.

Keywords: Burst firing; Egluetad (PubChem CID 156665); Mediodorsal thalamus; Metabotropic glutamate receptor; N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine (PubChem CID 9825084); N-Methylaspartate (PubChem CID 22880); Schizophrenia; Synaptic inhibition.

Fig. 1

Group II mGlu receptor activation reduces inhibition evoked in the MD. Ai Stimulation and recording sites for the PFC and MD electrodes, respectively. Aii Peristimulus time histograms (PSTHs) of responses of a spontaneously firing MD neurone (CMD31a) to electrical stimulation of the PFC under normal conditions, upon Group II agonist application, and recovery. 50 ms bins over 30 trials. Aiii Bars represent the mean % response (±SEM) under the same conditions (n = 5). *p < 0.05 when compared to control. Bi Stimulation and recording sites for the amygdala and MD electrodes, respectively. Bii PSTHs of responses of a spontaneously firing MD neurone (CMD02b) to electrical stimulation of the amygdala under normal conditions, upon Group II agonist application, and recovery. 50 ms bins over 30 trials. Biii Bars represent the mean % response (±SEM) under the same conditions (n = 6). *p < 0.05.

Fig. 2

Group II mGlu receptor activation increases evoked tonic firing in the MD. Ai Stimulation and recording sites for the PFC and MD electrodes, respectively. Aii PSTHs of responses of a tonically firing MD neurone (CMD22a) to electrical stimulation of the PFC under normal conditions, upon Group II agonist application alone, upon Group II agonist and mGlu2 PAM co-application, and recovery. 2 ms bins over 18 trials. Aiii Bars represent the mean % response (±SEM) under the same conditions (n = 5). *p < 0.05 when compared to control. Bi Stimulation and recording sites for the amygdala and MD electrodes, respectively. Bii PSTHs of responses of a tonically firing MD neurone (CMD34a) to electrical stimulation of the amygdala under normal conditions, upon Group II agonist application alone, upon Group II agonist and mGlu2 PAM co-application, and recovery. 2 ms bins over 18 trials. Biii Bars represent the mean % response (±SEM) under the same conditions (n = 5). *p < 0.05.

Fig. 3

Group II mGlu receptor activation decreases evoked burst firing in the MD. i Stimulation and recording sites for the PFC and MD electrodes, respectively. ii Illustrative raster display and PSTH of an MD neuron (CMD16a) burst firing in response to PFC stimulation. 20 ms bins over 30 trials. iii PSTHs of burst firing responses of the same MD neurone to electrical stimulation of the PFC under normal conditions, upon Group II agonist application alone, upon Group II agonist and mGlu2 PAM co-application, and recovery. Burst spikes, orange; non-burst spikes, black; 50 ms bins over 30 trials. iv Bars represent the mean % response (±SEM) under the same conditions (n = 5). *p < 0.05 when compared to control; n/s, not significant. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Group II mGlu receptor activation decreases evoked burst firing in the VB. i Vibrissal deflection schematic and recording site location for the VB electrode. ii Illustrative raster display and PSTH of a VB neuron (CVB78c) displaying both tonic and burst firing in response to vibrissal deflection. 20 ms bins over 30 trials. iii PSTHs of burst firing responses of the same VB neurone to vibrissal deflection under normal conditions, upon Group II agonist application alone, upon Group II agonist and mGlu2 PAM co-application, and recovery. Burst spikes, orange; tonic short-latency (8–50 ms) spikes, grey; total long-latency (300–1000 ms) spikes, black; 50 ms bins over 30 trials. iv Bars represent the mean % response (±SEM) under the same conditions (n = 5). *p < 0.05 when compared to control, unless otherwise indicated. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)