No abstract

Long-term potentiation (LTP) is a persistent strengthening of synaptic transmission in the brain and is arguably the most compelling cellular and molecular model for learning and memory. Previous work found that both AMPA receptors and exogenously expressed kainate receptors are equally capable of expressing LTP, despite their limited homology and their association with distinct auxiliary subunits, indicating that LTP is far more promiscuous than previously thought. What might these two subtypes of glutamate receptor have in common? Using a single-cell molecular replacement strategy, we demonstrate that the AMPA receptor auxiliary subunit TARP γ-8, via its PDZ-binding motif, is indispensable for both basal synaptic transmission and LTP. Remarkably, kainate receptors and their auxiliary subunits Neto proteins share the same requirement of PDZ-binding domains for synaptic trafficking and LTP. Together, these results suggest that a minimal postsynaptic requirement for LTP is the PDZ binding of glutamate receptors/auxiliary subunits to PSD scaffolding proteins.

Ambient GABA in the brain tonically activates extrasynaptic GABAAreceptors, and activity-dependent changes in ambient GABA concentration can also activate GABABreceptors. To investigate an interaction between postsynaptic GABABand GABAAreceptors, we recorded GABAAcurrents elicited by exogenous GABA (10 μm) from dentate gyrus granule cells (DGGCs) in adult rat hippocampal slices. The GABABreceptor agonist baclofen (20 μm) enhanced GABAAcurrents. This enhancement was blocked by the GABABreceptor antagonist CGP 55845 and intracellular solutions containing the GTP analog GDP-β-s, indicating that baclofen was acting on postsynaptic GABABreceptors. Modulation of GABAAcurrents by postsynaptic GABABreceptors was not observed in CA1 pyramidal cells or layer 2/3 cortical pyramidal neurons. Baclofen reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) but did not alter sIPSC amplitude or kinetics. Thus, GABAAreceptors activated at synapses were not modulated by postsynaptic GABABreceptors. In contrast, tonic GABA currents and currents activated by the GABAAreceptor δ subunit-selective agonist THIP (10 μm) were potentiated by baclofen. Our data indicate that postsynaptic GABABreceptors enhance the function of extrasynaptic GABAAreceptors, including δ subunit-containing receptors that mediate tonic inhibition in DGGCs. The modulation of GABAAreceptor function by postsynaptic GABABreceptors is a newly identified mechanism that will influence the inhibitory tone of DGGCs when GABABand GABAAreceptors are both activated.

The δ1 glutamate receptor (GluD1) was cloned decades ago and is widely expressed in many regions of the brain. However, its functional roles in these brain circuits remain unclear. Here, we find that GluD1 is required for both excitatory synapse formation and maintenance in the hippocampus. The action of GluD1 is absent in the Cbln2 knockout mouse. Furthermore, the GluD1 actions require the presence of presynaptic neurexin 1β carrying the splice site 4 insert (+S4). Together, our findings demonstrate that hippocampal synapse assembly and maintenance require a tripartite molecular complex in which the ligand Cbln2 binds with presynaptic neurexin 1β (+S4) and postsynaptic GluD1. We provide evidence that this mechanism may apply to other forebrain synapses, where GluD1 is widely expressed.

Long-term potentiation (LTP) is arguably the most compelling cellular model for learning and memory. While the mechanisms underlying the induction of LTP ('learning') are well understood, the maintenance of LTP ('memory') has remained contentious over the last 20 years. Here, we find that CaMKII contributes to synaptic transmission and is required LTP maintenance. Acute inhibition of CaMKII erases LTP and transient inhibition of CaMKII enhances subsequent LTP. These findings strongly support the role of CaMKII as a molecular storage devise.