Metabotropic Glutamate Receptors Drive Global Persistent Inhibition in the Visual Thalamus

Abstract

Within the dorsal lateral geniculate nucleus (dLGN) of the thalamus, retinal ganglion cell (RGC) projections excite thalamacortical (TC) cells that in turn relay visual information to the cortex. Local interneurons in the dLGN regulate the output of TC cells by releasing GABA from their axonal boutons and specialized dendritic spines. Here we examine the functional role of these highly-specialized interneurons and how they inhibit TC cells in mouse brain slices. It was widely thought that activation of metabotropic glutamate receptor type 5 (mGluR5) on interneuron spines leads to local GABA release restricted to sites receiving active RGC inputs. We reexamined experiments that supported this view, and found that in the presence of TTX, mGluR5 agonists evoked GABA release that could instead be explained by interneuron depolarization and widespread intracellular calcium increases. We also examined GABA release evoked by RGC activation and found that high-frequency stimulation induces a long-lasting subthreshold after depolarization, persistent firing, or prolonged plateau potentials in interneurons and evokes sustained GABA release. mGluR5 antagonists virtually eliminated sustained spiking and the resulting widespread calcium-signals, and reduced inhibition by over 50%. The remaining inhibition appeared to be mediated by a fraction of interneurons in which plateau potentials produced large and widespread calcium increases. Local calcium signals required for local GABA release were not observed. These findings indicate that, contrary to the previous view, RGC activation does not simply evoke localized GABA release by activating mGluR5, rather, synaptic activation of mGluR5 acts primarily by depolarizing interneurons and evoking widespread dendritic GABA release.

Functional Convergence at the Retinogeniculate Synapse

“…This established parasaggital slice preparation preferentially preserves connectivity between RGC axons that can be stimulated in the optic tract and dLGN neurons in the monocular zone of the dLGN. Mice were anesthetized with isoflurane; after decapitation the head was cooled, the brain was removed and immersed into oxygenated ice-cold cutting solution containing (in mM): 130 mM K-gluconate, 15 mM KCl, 0.05 mM EGTA, 20 mM HEPES, and 25 mM glucose (pH 7.4) with NaOH (Pressler and Regehr, 2013, Hong et al, 2014). This cutting solution improves viability of slices from mice up to and older than p100.…”

Causal Role of Thalamic Interneurons in Brain State Transitions: A Study Using a Neural Mass Model Implementing Synaptic Kinetics

“…This is in spite of the IN constituting around 20–25% of the total number of cells in almost all thalamic nuclei processing sensory information in mammals; around 47% of the synaptic afferents of the the IN are from the information carrying spiking neurons of the retina (Sherman, 2004; Jones, 2007). Moreover, the critical role of the IN in the visual signal processing by the LGN and information transmission in the retino-geniculo-cortical pathway is now well established (Dublin and Cleland, 1977; Wang et al, 2007; Babadi et al, 2010; Saalmann and Kastner, 2011; Wang et al, 2011a,b; Pressler and Regehr, 2013; Bastos et al, 2014; Hirsch et al, 2015); also, their physiology and spiking characteristics are now understood fairly well (Pape and McCormick, 1995; Zhu et al, 1999a,b; Cox et al, 2003). Thus, it is surprising that the importance of the causality of IN on brain rhythms is underestimated in experimental research, perhaps due to the lack of appropriate technology (Zhu et al, 1999a,b) that prevented proper recordings of the IN population dynamics.…”

Complex regulation of dendritic transmitter release from thalamic interneurons

“…This interpretation was further supported by the observation that the general mGluR agonist, ACPD, produced a very small membrane depolarization in somatic recordings from local interneurons [24,28]. However, the actions of mGluRs is actually more complicated: activation of group I mGluRs (mGluR 1 , mGluR 5 ) can produce a depolarization, whereas activation of group II mGluRs (mGluR 2 , mGluR 3 ) produces a hyperpolarization in interneurons [22,29]. Whether these specific subtypes can be selectively activated by synaptic afferents remains unclear, but could have important consequences on our understanding of mGluR-dependent actions on thalamocortical processing.…”

“…Whether these specific subtypes can be selectively activated by synaptic afferents remains unclear, but could have important consequences on our understanding of mGluR-dependent actions on thalamocortical processing. This is an relatively important issue consider that over the last several years, the independence between the distal events and somatic activity of the dLGN interneurons has been questioned based on studies indicating that somatic events can backpropagate into the dendritic arbor of the interneurons [19,29,30]. The functional significance of these differences is further discussed below ( Local vs.…”