Synapse-specific compartmentalization of signaling cascades for LTP induction in CA3 interneurons.

Inhibitory interneurons with somata in strata radiatum and lacunosum-molecular (SR/L-M) of hippocampal area CA3 receive excitatory input from pyramidal cells via the recurrent collaterals (RCs), and the dentate gyrus granule cells via the mossy fibers (MFs). Here we demonstrate that Hebbian long-term potentiation (LTP) at RC synapses on SR/L-M interneurons requires the concomitant activation of calcium-impermeable AMPARs (CI-AMPARs) and N-methyl-d-aspartate receptors (NMDARs). RC LTP was prevented by voltage clamping the postsynaptic cell during high-frequency stimulation (HFS; 3 trains of 100 pulses delivered at 100 Hz every 10s), with intracellular injections of the Ca(2+) chelator BAPTA (20mM), and with the NMDAR antagonist D-AP5. In separate experiments, RC and MF inputs converging onto the same interneuron were sequentially activated. We found that RC LTP induction was blocked by inhibitors of the calcium/calmodulin-dependent protein kinase II (CaMKII; KN-62, 10 µM or KN-93, 10 µM) but MF LTP was CaMKII independent. Conversely, the application of the protein kinase A (PKA) activators forskolin/IBMX (50 µM/25 µM) potentiated MF EPSPs but not RC EPSPs. Together these data indicate that the aspiny dendrites of SR/L-M interneurons compartmentalize synapse-specific Ca(2+) signaling required for LTP induction at RC and MF synapses. We also show that the two signal transduction cascades converge to activate a common effector, protein kinase C (PKC). Specifically, LTP at RC and MF synapses on the same SR/LM interneuron was blocked by postsynaptic injections of chelerythrine (10 µM). These data indicate that both forms of LTP share a common mechanism involving PKC-dependent signaling modulation.

Aspartate and glutamate mediate excitatory synaptic transmission in area CA1 of the hippocampus.

We examined whether L-aspartate (ASP) and L-glutamate (GLU) both function as endogenous neurotransmitters in area CA1 of the rat hippocampus. Radioligand displacement experiments using 3H-DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (3H-AMPA) to label AMPA/kainate receptors and 3H-cis-4-phosphonomethyl-2-piperidine carboxylic acid (3H-CGS-19755) to label NMDA receptors confirmed that GLU (Ki approximately 500 nM) but not ASP (Ki > 1 mM) has high affinity for AMPA/kainate receptors whereas GLU (Ki approximately 250 nM) and ASP (Ki approximately 1.3 microM) both have high affinity for NMDA receptors. Elevating extracellular potassium concentration (50 mM, 1 min) evoked the calcium-dependent release of both ASP (approximately 50% increase) and GLU (approximately 200% increase) from hippocampal slices and from minislices of area CA1. Reducing extracellular glucose concentration (0.2 mM) reduced GLU release, enhanced ASP release, and reduced AMPA/kainate receptor-mediated responses more than NMDA receptor-mediated responses (to 7% and 34% of control, respectively). Fiber volleys, antidromic population spikes, membrane potential, input resistance, and ATP content all were not affected by glucose reduction. Unlike low glucose, the inhibitory neuromodulator adenosine (5 microM), which reduces ASP and GLU release to a similar extent, reduced AMPA/kainate and NMDA receptor-mediated population EPSPs similarly (to 11% and 12% of control, respectively). AMPA/kainate and NMDA receptor-mediated population EPSPs were also similarly reduced by 0.4 microM TTX (to 32% and 22% of control, respectively) and similarly enhanced by 10 microM 4-aminopyridine (to 206% and 248% of control, respectively). Finally, NMDA receptor-mediated EPSCs measured by whole-cell recording decayed faster in low glucose (73 msec vs 54 msec) but not in adenosine (73 msec vs 78 msec). Together, these results confirm that ASP and GLU are both involved in excitatory synaptic transmission at the Schaffer collateral-commissural terminals in area CA1 of the rat hippocampus.

Actions of phosphomonoesters on CA1 hippocampal neurons as revealed by a combined electrophysiological and nuclear magnetic resonance study.

Phosphomonoesters (PMEs), precursors of membrane phospholipids, are found in high levels in the developing brain and Alzheimer's disease brain. The present study details the neurophysiological and metabolic effects of acute PME elevation on the Fisher 344 rat in vitro hippocampal slice. Two abundant PMEs, phosphoethanolamine (PE) and L-phosphoserine (PS), reliably altered properties of synaptic transmission at the Schaffer collateral/commissural-CA1 cell synapse. Specifically, PE reversibly depressed the amplitude of population EPSPs at millimolar concentrations but had no effect at micromolar concentrations. PS had biphasic effects on population EPSPs, inducing first a reduction followed by an enhancement of response amplitude. In contrast to PE, the effects of PS were not reversible; population EPSPs were augmented during the wash of PS, and the CA3 region generated evoked (but not spontaneous) epileptiform discharges. 31P nuclear magnetic resonance spectroscopy revealed enhanced slice uptake of PS compared to PE. There was no significant effect of PE on slice high-energy phosphates but incubation with PS significantly lowered slice phosphocreatine (PCr) and ATP concentrations. These observations indicate that the slice uptake of PS could be energy requiring and the enhanced response amplitude observed at 5 mM PS also could produce a drain on high-energy phosphates. Possible modes of PME action on hippocampal physiology are discussed.