Modulatory effects of activation of metabotropic glutamate receptors on GABAergic circuits in the mouse cortex

Abstract

Liu T, Petrof I, Sherman SM. Modulatory effects of activation of metabotropic glutamate receptors on GABAergic circuits in the mouse cortex. J Neurophysiol 111: 2287-2297, 2014. First published March 12, 2014 doi:10.1152/jn.00730.2013.-Metabotropic glutamate receptors (mGluRs) have a ubiquitous distribution in the central nervous system and often serve to regulate the release of neurotransmitters. We have previously shown that activation of both presynaptic and postsynaptic mGluRs can affect the gain of glutamatergic inputs in both thalamus and cortex. In the present study, we sought to determine the effect of mGluR activation on GABAergic inputs in cortex. Using whole cell recordings in a mouse slice preparation of either primary visual or auditory cortex (V1 or A1), we tested the effects on mGluRs by applying various agonists to the slice. Two pathways were tested in each area: the GABAergic inputs in layers 2/3 activated from layer 4 and the GABAergic inputs in layer 4 activated from adjacent layer 4. In both of these pathways, we found that activation of mGluRs significantly reduced the amplitude of the evoked inhibitory postsynaptic currents. Because the effects were not blocked by the addition of GDP␤S to the recording electrode, and because mGluR agonists did not affect responses to photostimulation of GABA in a low-Ca 2ϩ and high-Mg 2ϩ bathing solution, we concluded this reduction was due to activation of presynaptic mGluRs. Furthermore, using specific mGluR agonists, we found that group II mGluRs, but not group I mGluRs, were involved in these modulatory effects. Because similar results were found in both pathways in V1 and A1, a possible cortical pattern for these effects is suggested. cortical circuit; GABA; IPSC; mGluR; modulation METABOTROPIC GLUTAMATE RECEPTORS (mGluRs) are G proteincoupled receptors found in many areas of the mammalian brain (Hollmann and Heinemann 1994). Previous work from our laboratory has shown that activation of mGluRs either by agonist application or by stimulation of certain glutamatergic inputs reduces the gain of synaptic transmission in other glutamatergic inputs. Both presynaptic and postsynaptic mGluRs have been implicated in this phenomenon in various combinations [reviewed in Sherman (2014)].Recent studies have indicated the existence of mGluRs on GABAergic terminals, suggesting the possibility that activation of these receptors can modulate GABA release (Cartmell and Schoepp 2000;Pinheiro and Mulle 2008;Schoepp 2001). However, studies that tested this idea have produced a range of results. Activation of group II mGluRs has been shown to suppress GABAergic responses in hippocampus (Jouvenceau et al. 1995;Liu et al. 1993 Given the importance of GABAergic circuitry in cortex (Anderson et al. 2000;DeFelipe 1993;Ferster and Miller 2000;Haglund et al. 1992; Hamberger and van Gelder 1993;Hirsch and Martinez 2006;Marco et al. 1996;Monier et al. 2003;Sherwin 1999;Wood et al. 1979) and given the widespread presence of mGluRs in cortex, we sought to investigate the effects of...

Synaptic properties of the lemniscal and paralemniscal pathways to the mouse somatosensory thalamus

“…Examples of such modulation by class 2 inputs include control of tonic versus burst firing mode of thalamic relay cells (29,30) and affecting the EPSP amplitudes of class 1 inputs (1,(31)(32)(33)(34)(35). Also consistent with this modulatory role for class 2 inputs are in vivo studies showing that optogenetic manipulation of the class 2 corticogeniculate pathway from cortical layer 6 shows that gain control is one of its main roles (36,37).…”

Recruitment of inhibition and excitation across mouse visual cortex depends on the hierarchy of interconnecting areas

“…A perhaps surprising source of inhibition and disinhibition is glutamate. By activating pre- and postsynaptic metabotropic receptors in various neocortical circuits, glutamate release can induce suppression of GABA release and inhibition of L4 neurons, respectively ( Liu et al, 2014 ; Lee and Sherman, 2009 ). Thus, multiple, partially overlapping ( Gonchar et al, 2007 ) sources of inhibition may be differentially recruited depending on context, providing a multilayered control of cortical function ( Kepecs and Fishell, 2014 ; Pakan et al, 2016 ).…”

My prolonged collaboration with Ray Guillery

“…Evidence indeed exists that activation of modulatory glutamatergic inputs can affect the gain of driver inputs to neurons and also affect firing mode of thalamic relay cells (Godwin et al ., ; DePasquale & Sherman, ; Lam & Sherman, ; Liu et al ., , ). As noted above, other evidence indicates that the layer 6 corticothalamic pathway controls the gain of thalamocortical responsiveness (Lee & Sherman, , ; DePasquale & Sherman, ).…”