Effects of μ-Opioid Receptor Modulation on GABAB Receptor Synaptic Function in Hippocampal CA1

Activation of μ-opioid receptors (MORs) alters information coding, synaptic plasticity, and spatial memory in hippocampal CA1. In CA1, MORs act by inhibiting GABA release onto both GABAA and GABAB receptors exclusively. MOR activation can facilitate excitatory inputs in CA1 dendritic layers by inhibiting synaptic activation of GABAA receptors. In this study, we use voltage-sensitive dye imaging to show that MOR activation by the MOR agonist DAMGO suppressed GABAB inhibitory postsynaptic potentials in all layers of CA1. When stimulating excitatory input in stratum oriens (SO), stratum radiatum (SR), or stratum lacunosum-moleculare (SLM) with five pulses at 20 Hz in the presence of bicuculline (50 μM), DAMGO (1 μM) was most effective at increasing the amplitude of the last excitatory event. This effect was reversed by the MOR antagonist CTOP (1 μM) and occluded by the GABAB receptor agonist CGP 55845 (10 μM). DAMGO was less effective at increasing the amplitude of later excitatory events compared with the effect of CGP 55845. DAMGO was relatively ineffective at increasing the amplitude of excitatory inputs in SLM but had significantly greater effects on excitatory events as they propagated to stratum pyramidale (SP). When stimulating in SR, DAMGO was least effective at increasing excitatory amplitudes in SLM and most effective in SP and SO. Finally, DAMGO was equally effective at increasing excitatory activity amplitudes in all layers of CA1 after stimulating in SO. Therefore MOR suppresses GABAB synaptic hyperpolarizations in all layers of CA1 and most effectively facilitates excitatory activity in CA1 output layers.

GABAB-Receptor–Mediated Currents in Interneurons of the Dentate-Hilus Border

GABAB-receptor–mediated inhibition was investigated in anatomically identified inhibitory interneurons located at the border between the dentate gyrus granule cell layer and hilus. Biocytin staining was used to visualize the morphology of recorded cells. A molecular layer stimulus evoked a pharmacologically isolated slow inhibitory postsynaptic current (IPSC), recorded with whole cell patch-clamp techniques, in 55 of 63 interneurons. Application of the GABAB receptor antagonists, CGP 35348 (400 μM) or CGP 55845 (1 μM) to a subset of 25 interneurons suppressed the slow IPSC by an amount ranging from 10 to 100%. In 56% of these cells, the slow IPSC was entirely GABAB-receptor–mediated. However, in the remaining interneurons, a component of the slow IPSC was resistant to GABAB antagonists. Subtraction of this antagonist resistant current from the slow IPSC isolated the GABAB component (IPSCB). This IPSCB had a similar onset and peak latency to that recorded from granule cells but a significantly shorter duration. The GABAB agonist, baclofen (10 μM), produced a CGP 55845-sensitive outward current in 19 of 27 interneurons. In the eight cells that lacked a baclofen current, strong or repetitive ML stimulation also failed to evoke an IPSCB, indicating that these cells lacked functional GABABreceptor-activated potassium currents. In cells that expressed a baclofen current, the amplitude of this current was ∼50% smaller in interneurons with axons that projected into the granule cell dendritic layer (22.2 ± 5.3 pA; mean ± SE) than in interneurons with axons that projected into or near the granule cell body layer (46.1 ± 10.0 pA). Similarly, the IPSCBamplitude was smaller in interneurons projecting to dendritic (9.4 ± 2.7 pA) than perisomatic regions (34.3 ± 5.1 pA). These findings suggest that GABAB inhibition more strongly regulates interneurons with axons that project into perisomatic than dendritic regions. To determine the functional role of GABAB inhibition, we examined the effect of IPSPB on action potential firing and synaptic excitation of these interneurons. IPSPB and IPSPA both suppressed depolarization-induced neuronal firing. However, unlike IPSPA, suppression of firing by IPSPB could be easily overcome with strong depolarization. IPSPB markedly suppressed N-methyl-d-aspartate but not AMPA EPSPs, suggesting that GABAB inhibition may play a role in regulating slow synaptic excitation of these interneurons. Heterogeneous expression of GABAB currents in hilar border interneurons therefore may provide a mechanism for the differential regulation of excitation of these cells and thereby exert an important role in shaping neuronal activity in the dentate gyrus.

Net Interaction Between Different Forms of Short-Term Synaptic Plasticity and Slow-IPSPs in the Hippocampus and Auditory Cortex

Buonomano, Dean V. and Michael M. Merzenich. Net interaction between different forms of short-term synaptic plasticity and slow-IPSPs in the hippocampus and auditory cortex. J. Neurophysiol. 80: 1765–1774, 1998. Paired-pulse plasticity is typically used to study the mechanisms underlying synaptic transmission and modulation. An important question relates to whether, under physiological conditions in which various opposing synaptic properties are acting in parallel, the net effect is facilitatory or depressive, that is, whether cells further or closer to threshold. For example, does the net sum of paired-pulse facilitation (PPF) of excitatory postsynaptic potentials (EPSPs), paired-pulse depression (PPD) of inhibitory postsynaptic potentials (IPSPs), and the hyperpolarizing slow IPSP result in depression or facilitation? Here we examine how different time-dependent properties act in parallel and examine the contribution of γ-aminobutyric acid-B (GABAB) receptors that mediate two opposing processes, the slow IPSP and PPD of the fast IPSP. Using intracellular recordings from rat CA3 hippocampal neurons and L-II/III auditory cortex neurons, we examined the postsynaptic responses to paired-pulse stimulation (with intervals between 50 and 400 ms) of the Schaffer collaterals and white matter, respectively. Changes in the amplitude, time-to-peak (TTP), and slope of each EPSP were analyzed before and after application of the GABAB antagonist CGP-55845. In both CA3 and L-II/III neurons the peak amplitude of the second EPSP was generally depressed (further from threshold) compared with the first at the longer intervals; however, these EPSPs were generally broader and exhibited a longer TTP that could result in facilitation by enhancing temporal summation. At the short intervals CA3 neurons exhibited facilitation of the peak EPSP amplitude in the absence and presence of CGP-55845. In contrast, on average L-II/III cells did not exhibit facilitation at any interval, in the absence or presence of CGP-55845. CGP-55845 generally “erased” short-term plasticity, equalizing the peak amplitude and TTP of the first and second EPSPs at longer intervals in the hippocampus and auditory cortex. These results show that it is necessary to consider all time-dependent properties to determine whether facilitation or depression will dominate under intact pharmacological conditions. Furthermore our results suggest that GABAB-dependent properties may be the major contributor to short-term plasticity on the time scale of a few hundred milliseconds and are consistent with the hypothesis that the balance of different time-dependent processes can modulate the state of networks in a complex manner and could contribute to the generation of temporally sensitive neural responses.