Activation of Synaptic Group II Metabotropic Glutamate Receptors Induces Long-Term Depression at GABAergic Synapses in CNS Neurons

Abstract

Metabotropic glutamate receptor (mGluR)-dependent homosynaptic long-term depression (LTD) has been studied extensively at glutamatergic synapses in the CNS. However, much less is known about heterosynaptic long-term plasticity induced by mGluRs at inhibitory synapses. Here we report that pharmacological or synaptic activation of group II mGluRs (mGluR II) induces LTD at GABAergic synapses without affecting the excitatory glutamatergic transmission in neurons of the chicken cochlear nucleus. Coefficient of variation and failure rate analysis suggested that the LTD was expressed presynaptically. The LTD requires presynaptic spike activity, but does not require the activation of NMDA receptors. The classic cAMP-dependent protein kinase A signaling is involved in the transduction pathway. Remarkably, blocking mGluR II increased spontaneous GABA release, indicating the presence of tonic activation of mGluR II by ambient glutamate. Furthermore, synaptically released glutamate induced by electrical stimulations that concurrently activated both the glutamatergic and GABAergic pathways resulted in significant and constant suppression of GABA release at various stimulus frequencies (3.3, 100, and 300 Hz). Strikingly, low-frequency stimulation (1 Hz, 15 min) of the glutamatergic synapses induced heterosynaptic LTD of GABAergic transmission, and the LTD was blocked by mGluR II antagonist, indicating that synaptic activation of mGluR II induced the LTD. This novel form of long-term plasticity in the avian auditory brainstem may play a role in the development as well as in temporal processing in the sound localization circuit.

Interplay between low threshold voltage-gated K+ channels and synaptic inhibition in neurons of the chicken nucleus laminaris along its frequency axis

“…PPR paradigm, however, is not effective in studying synaptic inhibition of NL neurons due to dramatic fluctuations in IPSC peak amplitude under control conditions (Kuo et al, 2009; Tang et al, 2013). Analyses of 1/CV 2 of IPSPs ( Figures 6H,I ) and IPSCs ( Figure 8J ) did not show significant differences in the percent change of 1/CV 2 caused by DTX between CF regions.…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Group III consists of mGluR4 and mGluR6-mGluR8, which are also largely presynaptic. Of these, group II and III mGluRs are inhibitory autoreceptors on glutamatergic terminals (Conn and Pin, 1997;Testa et al, 1998;Niswender and Conn, 2010;Kupchik et al, 2011b) and heteroreceptors on dopaminergic (Hu et al, 1999;Karasawa et al, 2006) and GABAergic terminals (Kosinski et al, 1999;Karasawa et al, 2006;Mao et al, 2013;Tang et al, 2013). The heteroreceptors will not be further discussed here (for review, see Mao et al, 2013).…”

The balancing act of GABAergic synapse organizers

“…Presynaptic activation of the type II mGluRs causes inhibitory longterm depression (iLTD) [69], while decreased postsynaptic protein kinase A (PKA) activity in conjunction with calcineurin expression via A-kinase anchoring protein (AKAP) regulates iLTD to trigger the internalization of GABA A receptors [70]. Retrograde endocannabinoid (eCB) signaling mediates presynaptic iLTD (eCB-LTD) via the presynaptic active zone proteins RIM1a/Rab3B and P/Q-type voltage-gated calcium channels (VGCCs; reviewed in [71]).…”