GluK1 inhibits calcium dependent and independent transmitter release at associational/commissural synapses in area CA3 of the hippocampus

Abstract

CA3 pyramidal cells receive three main excitatory inputs: the first one is the mossy fiber input, synapsing mainly on the proximal apical dendrites. Second, entorhinal cortex cells form excitatory connections with CA3 pyramidal cells via the perforant path in the stratum lacunosum moleculare. The third input involves the ipsi-and contralateral connections, termed the associational/commissural (A/C) pathway terminating in the stratum radiatum of CA3, thus forming a feedback loop within this region. Since this excitatory recurrent synapse makes the CA3 region extremely prone to seizure development, understanding the regulation of synaptic strength of this connection is of crucial interest. Several studies suggest that kainate receptors (KAR) play a role in the regulation of synaptic strength. Our aim was to characterize the influence of KAR on A/C synaptic transmission: application of ATPA, a selective agonist of the GluK1 KAR, depressed the amplitude fEPSP without affecting the size of the fiber volley. Blockade of GABA receptors had no influence on this effect, arguing against the influence of interneuronal KARs. Pharmacological and genetic deletion studies could show that this effect was selectively due to GluK1 receptor activation. Several lines of evidence, such as PPF changes, coefficient of variance-analysis and glutamate uncaging experiments strongly argue for a presynaptic locus of suppression. This is accompanied by an ATPA-mediated reduction in Ca(2+) influx at excitatory synaptic terminals, which is most likely mediated by a G-Protein dependent mechanism, as suggested by application of pertussis toxin. Finally, analysis of miniature EPSCs in the presence and absence of extracellular Ca(2+) suggest that presynaptic KAR can also reduce transmitter release downstream and therefore independent of Ca(2+) influx.

Recurrent synapses and circuits in the CA3 region of the hippocampus: an associative network

“…Receptors for the metabotropic glutamate receptor, mGluR7, expressed at active zones facing interneurons but not principal cells (Shigemoto et al, 1996) specifically control the excitation of inhibitory cells (Scanziani et al, 1998). The kainate receptor GluK1, reduces release by effects on both Ca entry and on G-protein mediated stages in transmitter release (Salmen et al, 2012). In contrast, presynaptic NMDA receptors enhance Ca entry and facilitate release at some synapses made by CA3 collaterals(McGuinness L et al, 2010).…”

Kainate Receptors Play a Role in Modulating Synaptic Transmission in the Olfactory Bulb

“…The authors concluded that modulation of glutamate release by GluK1-containing KARs in the spinal cord depends on the activation of a G protein. In the hippocampus, ATPA (1 μM) decreased fEPSP amplitude and reduced calcium influx at excitatory synaptic terminals (Salmen et al, 2012), which was abolished by inactivation of G proteins with pertussis toxin.…”

Kainate Receptors in Health and Disease

“…Indeed, expression of GluK1 in SHSY5 neuroblastoma cells was sufficient to reconstitute metabotropic activity of KARs, as evaluated by the G protein and PKC activation inducing internalization of KARs from the membrane (Rivera et al, 2007). Recent experiments confirmed the involvement of GluK1 in the metabotropic control of glutamate release (Segerstrå le et al, 2010;Salmen et al, 2012). However, a biochemical interaction between GluK5 and a G aq protein was identified in biochemical experiments (Ruiz et al, 2005).…”