TRPM3 expression and control of glutamate release from primary vagal afferent neurons.

Vagal afferent fibers contact neurons in the nucleus of the solitary tract (NTS) and release glutamate via three distinct release pathways: synchronous, asynchronous, and spontaneous. The presence of TRPV1 in vagal afferents is predictive of activity-dependent asynchronous glutamate release along with temperature-sensitive spontaneous vesicle fusion. However, pharmacological blockade or genetic deletion of TRPV1 does not eliminate the asynchronous profile and only attenuates the temperature-dependent spontaneous release at high temperatures (>40˚C), indicating additional temperature-sensitive calcium conductance(s) contributing to these release pathways. The transient receptor potential cation channel melastatin subtype 3 (TRPM3) is a calcium-selective channel which functions as a thermosensor (30-37˚C) in somatic primary afferent neurons. We predict TRPM3 is expressed in vagal afferent neurons and contributes to asynchronous and spontaneous glutamate release pathways. We investigated these hypotheses via measurements on cultured nodose neurons and in brainstem slice preparations containing vagal afferent to NTS synaptic contacts. We found histological and genetic evidence that TRPM3 is highly expressed in vagal afferent neurons. The TRPM3-selective agonist, pregnenolone sulfate, rapidly and reversibly activated the majority (~70%) of nodose neurons; most of which also contained TRPV1. We confirmed the role of TRPM3 with pharmacological blockade and genetic deletion. In the brain, TRPM3 signaling strongly controlled both basal and temperature-driven spontaneous glutamate release. Surprisingly, genetic deletion of TRPM3 did not alter synchronous nor asynchronous glutamate release. These results provide convergent evidence that vagal afferents express functional TRPM3 that serves as an additional temperature-sensitive calcium conductance involved in controlling spontaneous glutamate release onto neurons in the NTS.

Calcium conductance-dependent network synchronization is differentially modulated by firing frequency

Synchronous oscillations in certain frequencies of the sub-thalamic nucleus (STN) neurons are closely related to the physical symptoms of Parkinson’s disease (PD). Recent results have highlighted the importance of calcium channels in the synchronization properties and regulation of STN neurons. In this paper, a novel hybrid neuron model which can capture the electrophysiological signature of neurons with low or high density of calcium channels is used to explore the synchronization propensity and regulation by firing frequencies of neurons. Numerical simulations show that the synchronization propensity of networks consisting of the novel hybrid neurons is quite distinguishing in low and high calcium conductance modes, especially, the synchronization can be differentially modulated by network frequencies in the two modes. By analyzing the firing frequency and phase response curve of the individual neuron, we find that a single parameter of the hybrid neuron, which is a direct image of the calcium conductance, is crucial in determining the excitability and response properties of the neuron. Different phase response properties of single neurons in different calcium conductance modes lead to network synchronization discrepancies.

Are sleep spindles poised on supercritical Hopf bifurcations?

ABSTRACTSleep spindles are recognized as an important intermediate state of long term memory formation. During non REM sleep, large numbers of thalamic relay neurons synchronize their spike bursts for one half to two seconds, entraining many millions of neurons, and constituting a sleep spindle. Here we study spindle amplification, entrainment, synchronization and decay. Relay neurons have both a high resting state near −60 millivolts (mV) and low resting state near −75 mV. Due to the neuron’s sodium conductance, low-threshold calcium conductance, and calcium-dependent H conductance, it exhibits a number of bifurcations, like its supercritical Hopf at −61 mV. Here low-threshold calcium conductance destabilizes membrane potential to birth a small limit-cycle in the 7-16 Hz range. Supercritical Hopfbifurcations are the underlying mechanism for amplification and frequency selectivity in hearing: hair cells are forced by sinusoidal input currents driving their mainly capacitive loads, with the forcing currents locking at 90 degree phase leads with respect to their oscillating membrane potentials. Here we model a small part of a spindle, with 6 cross-coupled relay neurons all poised on Hopfbifurcations. One neuron is forced by a weak noisy train of periodic current impulses that typically lock at a 90 degree phase lead with respect to its voltage oscillation. It then drives its neighbors, causing them to drive each other at much smaller phase angles, usually less than ±10 degrees. The system of Hopf oscillators exhibit small signal amplification and frequency selectivity, high degrees of synchronization and noise rejection, and switch-ability. These argue in favor of spindling relay neurons poising on, or very near to, supercritical Hopfbifurcations. Also, during the phase-locking of their spike bursts, calcium conductance oscillations increase internal calcium, which turns on slow H current. This depolarizes the relay cells, pushing them below their Hopfbifurcations and terminating the spindle.