Inhibitory Interconnections Control Burst Pattern and Emergent Network Synchrony in Reticular Thalamus

PTX increases the number, but not the duration, of RE cell bursts during evoked thalamic oscillations in vitro. a, Intracellular recording from an RE cell (top) and simultaneous extracellular recording from TC cells (bottom) during evoked oscillations in control conditions (left), during application of 50 μm PTX (middle), and after PTX washout (right). The stimulus artifact is visible at the left of each trace. b, Bursts labeled 1, 2, etc. in a are plotted here on an expanded time scale. Again, the left panel shows control traces, the middle panel shows PTX traces, and the right panel shows wash traces. Calibration: top, 1 sec, 25 mV; bottom, 20 msec, 25 mV. Resting membrane potential, -82 mV.

Effects of locally applied PTX and bath-applied CZP on thalamic oscillations in vitro. a, Intracellular recording from an RE cell (top), and simultaneous extracellular recording from TC cells (bottom) during evoked oscillations in control conditions (left), after local application of 100 μm PTX to the RE nucleus (middle), and after PTX washout (right). Locally applied PTX reversibly increases the number of RE cell bursts per oscillation. Calibration: 1 sec, 25 mV. Resting membrane potential, -88 mV. b, Intracellular recording from an RE cell (top) and simultaneous extracellular recording from TC cells (bottom) during evoked oscillations in control conditions (left), after bath application of 100 nm CZP (middle), and during subsequent application of 50 μm PTX (right). CZP decreases the number of RE cell bursts per oscillation. The subsequent application the GABA_AR antagonist PTX has the opposite effect. Calibration: 1 sec, 25 mV. Resting membrane potential, -62 mV.

Intra-RE inhibition controls the number of RE cell bursts, but not their duration. a, Average change in the number of RE cell bursts per oscillation after bath application of 50 μm PTX (black bar), local application of 100 μm PTX to the RE nucleus (gray bar), or bath application of 100 nm CZP (hatched bar). Blocking intra-RE inhibition significantly increases the number of bursts, whereas CZP, which augments intra-RE inhibition, significantly decreases the number of bursts (^*p < 0.05; ^**p < 0.01). b, Average change in the number of spikes per RE cell burst during evoked oscillations in the same three conditions. Pharmacological manipulations of intra-RE inhibition alter the number of spikes per burst by less than one spike, and only in one case are these changes statistically significant. (Number of cells per condition varies between 5 and 14; see Results for details.)

Intra-RE inhibition controls RE cell responsiveness. a, Examples of the last EPSPs detected immediately preceding each RE cell burst. Only the final few EPSPs preceding each burst are shown. Traces are shown for each of four consecutive bursts during an evoked oscillation. A circle is superimposed on each trace, centered on the peak of the detected EPSP. The resting membrane potential of this RE cell was -82 mV, and for this cell the spike threshold, i.e., the point at which the membrane potential begins to rise very steeply, was always between -59 and -56 mV. b, The probability that EPSPs of a given amplitude elicited bursts in the RE cell depicted in a, in control conditions (solid black line), PTX (gray line), and CZP (dotted black line). At each membrane potential between 2 and 8 mV, bursts were most frequently elicited in PTX and least often in CZP. c, The average change in the probability that EPSPs <10 mV in amplitude successfully elicit bursts after application of CZP (n = 3 experiments) or PTX (n = 3 experiments).

CZP desynchronizes RE cell bursts during evoked oscillations in vitro. a, Times of intracellularly recorded RE cell spikes (bars) superimposed on the TC cell extracellular spike rate (ratemeter, line) for one oscillation in control conditions (left) and after CZP application (right). Calibration: 500 msec, 400 spikes/sec. b, Absolute timing difference between each of these RE cell spikes and the nearest burst in the TC cell ratemeter (see Materials and Methods). a and b are plotted on the same horizontal time scale, so each cross in b represents the phase of the intracellular spike located directly above it in a.

Intra-RE inhibition desynchronizes model RE cells. The responses of two model RE cells to identical, 10 Hz trains of EPSCs, are shown when intra-RE inhibition is absent (left) and when the two cells connected by inhibitory synapses with conductances of 100 nS (right). The two RE cells are identical except for their leak conductances, so that the resting membrane potentials of the cells depicted in the top and bottom traces, respectively, are -76 and -73 mV. For the case that includes intra-RE inhibition (right), the GABA_AR conductance is plotted below the voltage trace for each RE cell. When intra-RE inhibition is present, it desynchronizes bursting in the two RE cells, by vetoing (^*) excitatory input on alternate cycles.

Intra-RE inhibition desynchronizes oscillations in a simulated thalamic network. a, Activity in a network with intra-RE inhibition (left; GABA_A conductance on each RE cell, 50 nS) and a network without intra-RE inhibition (right). The top panels show the times at which RE and TC cells at different locations in the networks spike, and the bottom panels shows the summed activity of TC cells throughout each network as a function of time. Activity was initiated in both networks by instantaneously depolarizing two-thirds of the RE cells above their threshold for bursting. b, Summed TC cell activity in networks with postsynaptic GABA_BRs on TC cells (the GABA_A and GABA_B conductances on each TC cell are 40 and 20 nS, respectively). As in a, desynchronized spindle-like oscillations occur when intra-RE inhibition is present (left, GABA_A conductance on each RE cell = 100 nS). In contrast to a, the epileptiform discharges that occur in the absence of intra-RE inhibition (right, 3.7 Hz) are much slower than the spindle-like oscillations (left, 9.1 Hz).