Cortical afferents onto the nucleus Reticularis thalami promote plasticity of low-threshold excitability through GluN2C-NMDARs

Abstract

Thalamus and cortex represent a highly integrated processing unit that elaborates sensory representations. Interposed between cortex and thalamus, the nucleus Reticularis thalami (nRt) receives strong cortical glutamatergic input and mediates top-down inhibitory feedback to thalamus. Despite growing appreciation that the nRt is integral for thalamocortical functions from sleep to attentional wakefulness, we still face considerable gaps in the synaptic bases for cortico-nRt communication and plastic regulation. Here, we examined modulation of nRt excitability by cortical synaptic drive in Ntsr1-Cre x ChR2tg/+ mice expressing Channelrhodopsin2 in layer 6 corticothalamic cells. We found that cortico-nRt synapses express a major portion of NMDA receptors containing the GluN2C subunit (GluN2C-NMDARs). Upon repetitive photoactivation (10 Hz trains), GluN2C-NMDARs induced a long-term increase in nRt excitability involving a potentiated recruitment of T-type Ca2+ channels. In anaesthetized mice, analogous stimulation of cortical afferents onto nRt produced long-lasting changes in cortical local field potentials (LFPs), with delta oscillations being augmented at the expense of slow oscillations. This shift in LFP spectral composition was sensitive to NMDAR blockade in the nRt. Our data reveal a novel mechanism involving plastic modification of synaptically recruited T-type Ca2+ channels and nRt bursting and indicate a critical role for GluN2C-NMDARs in thalamocortical rhythmogenesis.

A thalamic reticular circuit for head direction cell tuning and spatial navigation

“…2E1, E2). NMDA/AMPA ratios were comparable to previous studies in 148 sensory TRN and thalamus (Fernandez et al, 2017). Moreover, the TRN-EPSCs had a twice-149…”

Modulation of Burst Firing of Neurons in Nucleus Reticularis of the Thalamus by GluN2C-Containing NMDA Receptors

“…This finding is also supported by minimal stimulation studies that suggest the presence of NMDA receptors with lower Mg 21 sensitivity at both of these synaptic inputs onto nRT neurons (Deleuze and Huguenard, 2016). Recently it has been identified that the GluN2C-containing receptors at the cortico-nRT synapses may induce a form of plasticity that involves Ca 21 entry and facilitation of low-threshold Ca 21 channels, potentially T-type channels (Fernandez et al, 2017). However, because of the use of pharmacological agents that modulate both GluN2C-and GluN2Dcontaining receptors and lack of use of knockout approach, it is possible that some of these effects are mediated by GluN2D-containing receptors, which are also enriched in nRT neurons (Yamasaki et al, 2014;Alsaad et al, 2019).…”

“…The neurons in nRT receive glutamatergic collaterals from cortical pyramidal neurons and thalamic relay neurons. Using pharmacological tools, it has been suggested that both thalamo-nRT and cortico-nRT synapses express GluN2C-containing NMDA receptors (Astori and Luthi, 2013;Fernandez et al, 2017). This finding is also supported by minimal stimulation studies that suggest the presence of NMDA receptors with lower Mg 21 sensitivity at both of these synaptic inputs onto nRT neurons (Deleuze and Huguenard, 2016).…”

“…These features appear to be suited for tonic activity. The neurons in the nRT regions has been found to be rich in the GluN2C and GluN2D subunits of the NMDA receptors (Watanabe et al, 1992;Buller et al, 1994;Monyer et al, 1994;Lin et al, 1996;Wenzel et al, 1997;Zhang et al, 2012;Astori and Luthi, 2013;Yamasaki et al, 2014;Fernandez et al, 2017;Ravikrishnan et al, 2018;Alsaad et al, 2019). Neurons in nRT have been shown to exhibit NMDA receptor currents that have lower Mg 21 sensitivity, whereas nRT neurons in GluN2C knockout (KO) mice show a shift to higher sensitivity to Mg 21 blockade (Zhang et al, 2009(Zhang et al, , 2012Deleuze and Huguenard, 2016).…”

Roles of GluN2C in cerebral ischemia: GluN2C expressed in different cell types plays different role in ischemic damage

“…Therefore, one important property of GluN2C receptors is the lower sensitivity to Mg 2+ block compared to GluN2A and GluN2B receptors (Burnashev et al, ; Kuner & Schoepfer, ; Monyer, Burnashev, Laurie, Sakmann, & Seeburg, ; Monyer et al, ). This property allows GluN2C receptors to be activated by ambient glutamate at resting membrane potential and contributes to higher NMDAR activity at resting potential in some brain regions, such as in layer 4 of barrel cortex (Binshtok, Fleidervish, Sprengel, & Gutnick, ) and reticular thalamic nuclei (Fernandez et al, ; Zhang, Llinas, & Lisman, ).…”