fg-9041 and eglumetad

Mechanisms that control neuronal gain allow for adaptive rescaling to synaptic inputs of varying strengths or frequencies. Here, we show that unitary IPSPs (uIPSPs) modulate gain and unitary EPSP (uEPSP)-action potential coupling in mossy cells (MCs) from rat hippocampal slices. Mossy fibre-evoked uEPSCs were large, facilitated and were suppressed by the group II metabotropic glutamate agonist LY354740. Conversely, uIPSCs were smaller, depressed and were not affected by LY354740, but exerted strong inhibitory control over uEPSP-action potential coupling. The IPSC reversal potential was determined by gramicidin perforated patch recordings to be -65.3 +/- 5.0 mV, lying between the resting membrane potential (-75.3 +/- 1.1 mV) and the action potential threshold (-56.5 +/- 2.4 mV). When applied at theta frequency (10 Hz), uIPSPs increased the offset of the MC input-output response to depolarizing current injection, but also increased gain, maximal firing rate and the slope of the depolarization preceding action potentials. These effects were unchanged by the Ca2+ and HCN channel blockers mibefradil and ZD7288, respectively. The height and maximal slope of MC action potentials during tonic depolarization were also increased by uIPSPs, and the decay of uIPSP conductances injected by dynamic clamp at subthreshold membrane potentials was prolonged by TTX. Application of the muscarinic agonist pilocarpine mimicked the effect of IPSPs on MC maximal firing rate, and action potential height and slope, and this was reversed by the GABA(A) antagonist gabazine. Thus, uIPSPs can increase neuronal gain under hyperexcitable conditions, and this effect is probably due to the de-inactivation of a TTX-sensitive voltage-dependent Na+ conductance.

Topics: 2-Amino-5-phosphonovalerate; Action Potentials; Animals; Bridged Bicyclo Compounds; Cell Membrane; Electric Capacitance; Electric Impedance; Excitatory Postsynaptic Potentials; Hippocampus; Inhibitory Postsynaptic Potentials; Interneurons; Male; Mossy Fibers, Hippocampal; Neurons; Patch-Clamp Techniques; Pilocarpine; Pyridazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Sodium Channels; Synaptic Transmission; Tetrodotoxin

I have compared the effects of group II or III metabotropic glutamate receptor (mGluR) activation on monosynaptic excitatory responses recorded intracellularly from CA1 pyramidal neurons of rat hippocampus and evoked by perforant pathway stimulation in vitro. The excitatory postsynaptic currents (EPSCs) were reduced either by the group II mGluR agonist LY354740 (500 nM, 31 +/- 6% of control) or by the group III agonist L-AP4 (400 microM, 53 +/- 5% of control). Both drugs enhanced EPSC paired-pulse facilitation (range 125-189% of control). These effects were blocked by the broad-spectrum mGluR antagonist LY341495 (1 or 20 microM) which when applied alone did not significantly change the EPSCs elicited at low (0.1-0.2 Hz) or higher (1-100 Hz) frequency of stimulation. Prior reduction of the EPSCs induced by L-AP4 did not occlude the subsequent inhibition elicited by LY354740. The effect of LY354740, but not that of L-AP4, was blocked in the presence of the cAMP analogue Sp-cAMPS (20 microM) and with the K(+) channel antagonist alpha-dendrotoxin (125 nM). In contrast, the effect of L-AP4, but not that of LY354740, was prevented by the calmodulin inhibitor ophiobolin A (25 microM) and with the N-type Ca(2+) channel antagonist omega-conotoxin-GVIA (1 microM). In the presence of the P/Q type Ca(2+) channel antagonist omega-agatoxin-IVA (400 nM), the EPSCs were depressed either by LY354740 or by L-AP4. Groups II and III mGluRs are segregated at the presynaptic terminal, and there are distinct differences between the properties of the presynaptic inhibition mediated by these two groups of receptors.

Topics: Amino Acids; Aminobutyrates; Animals; Bridged Bicyclo Compounds; Calcium Channel Blockers; Cyclic AMP; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Interactions; Elapid Venoms; Electric Stimulation; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Antagonists; Hippocampus; In Vitro Techniques; Membrane Potentials; Neural Inhibition; omega-Conotoxin GVIA; Perforant Pathway; Phosphinic Acids; Propanolamines; Quinoxalines; Rats; Receptors, Metabotropic Glutamate; Statistics, Nonparametric; Synaptic Transmission; Thionucleotides; Time Factors; Xanthenes