Balanced ionotropic receptor dynamics support signal estimation via voltage-dependent membrane noise

Encoding behaviorally relevant stimuli in a noisy background is critical for animals to survive in their natural environment. We identify core biophysical and synaptic mechanisms that permit the encoding of low-frequency signals in pyramidal neurons of the weakly electric fish Apteronotus leptorhynchus, an animal that can accurately encode even miniscule amplitude modulations of its self-generated electric field. We demonstrate that slow NMDA receptor (NMDA-R)-mediated excitatory postsynaptic potentials (EPSPs) are able to summate over many interspike intervals (ISIs) of the primary electrosensory afferents (EAs), effectively eliminating the baseline EA ISI correlations from the pyramidal cell input. Together with a dynamic balance of NMDA-R and GABA-A-R currents, this permits stimulus-evoked changes in EA spiking to be transmitted efficiently to target electrosensory lobe (ELL) pyramidal cells, for encoding low-frequency signals. Interestingly, AMPA-R activity is depressed and appears to play a negligible role in the generation of action potentials. Instead, we hypothesize that cell-intrinsic voltage-dependent membrane noise supports the encoding of perithreshold sensory input; this noise drives a significant proportion of pyramidal cell spikes. Together, these mechanisms may be sufficient for the ELL to encode signals near the threshold of behavioral detection.

Characteristics and Organization of Discharge Properties in Rat Hindlimb Motoneurons

The discharge properties of hindlimb motoneurons in ketamine–xylazine anesthetized rats were measured to assess contributions of persistent intrinsic currents to these characteristics and to determine their distribution in motoneuron pools. Most motoneurons (30/37) responded to ramp current injections with adapting patterns of discharge and the frequency–current ( f– I) relations of nearly all motoneurons included a steep subprimary range of discharge. Despite the prevalence of adapting f– I relations, responses included indications that persistent inward currents (PICs) were activated, including increased membrane noise and prepotentials before discharge, as well as counterclockwise hysteresis and secondary ranges in f– I relations. Examination of spike thresholds and afterhyperpolarization (AHP) trajectories during repetitive discharge revealed systematic changes in threshold and trajectory within the subprimary, primary, and secondary f– I ranges. These changes in the primary and secondary ranges were qualitatively similar to those described previously for cat motoneurons. Within the subprimary range, AHP trajectories often included shallow approaches to threshold following recruitment and slope of the AHP ramp consistently increased until the subprimary range was reached. We suggest that PICs activated near recruitment contributed to these slope changes and formation of the subprimary range. Discharge characteristics were strongly correlated with motoneuron size, using input conductance as an indicator of size. Discharge adaptation, recruitment current, and frequency increased with input conductance, whereas both subprimary and primary f– I gains decreased. These results are discussed with respect to potential mechanisms and their functional implications.

Pharmacology of Nicotinic Receptors in PreBötzinger Complex That Mediate Modulation of Respiratory Pattern

Nicotine regulates respiratory pattern by modulating excitatory neurotransmission affecting inspiratory neurons within the preBötzinger Complex (preBötC). The nicotinic acetylcholine receptor (nAChR) subtypes mediating these effects are unknown. Using a medullary slice preparation from neonatal rat, we recorded spontaneous respiratory-related rhythm from the hypoglossal nerve (XIIn) and patch-clamped inspiratory neurons in the preBötC simultaneously. The α7 nAChR antagonists α-bungarotoxin or methyllycaconitine (MLA) had little effect on the actions of low concentrations of nicotine (0.5 μM), which included an increase in respiratory frequency; a decrease in amplitude of XIIn inspiratory bursts; a tonic inward current associated with an increase in membrane noise; an increase in the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), and; a decrease in the amplitude of inspiratory drive current in voltage-clamped preBötC inspiratory neurons. These nicotinic actions were completely reversed by dihydro-β-erythroidine (DH-β-E) or hexamethonium and reduced by d-tubocurarine. Comparable concentrations of RJR-2403 (0.5–1 μM), an agonist selective for α4β2 nAChRs, increased respiratory frequency to 186% and decreased the amplitude of XIIn inspiratory bursts to 83% of baseline. In voltage-clamped preBötC inspiratory (including pacemaker) neurons, RJR-2403 induced a tonic inward current of −15.2 pA associated with an increase in membrane noise, increased the frequency to 157% and amplitude to 106% of spontaneous EPSCs, and decreased the amplitude of inspiratory drive current to 80% of baseline. MLA had little effect on RJR-2403 actions, while DH-β-E completely reversed them. These results suggest that the predominant subtype of nAChRs in preBötC in neonatal rats that mediates the modulation of respiratory pattern by low concentrations of nicotine is an α4β2 combination and not an α7 subunit homomer. We do not exclude the possibility that co-assembly of α4β2 with other subunits or other nAChR subtypes are also expressed in preBötC neurons. The parallel changes in the cellular and systems level responses induced by different nicotinic agonists and antagonists support the idea that modulation of excitatory neurotransmission affecting preBötC inspiratory neurons is a mechanism underlying the cholinergic regulation of respiratory pattern ( Shao and Feldman 2001 ). This study provides a useful model system for evaluating potential therapeutic cholinergic agents for their respiratory effects and side effects.