Faculty Bibliography

In the suprachiasmatic nucleus (SCN), the master circadian pacemaker, neurons show circadian variations in firing frequency. There is also considerable synchrony of spiking across SCN neurons on a scale of milliseconds, but the mechanisms are poorly understood. Using paired whole-cell recordings, we have found that many neurons in the rat SCN communicate via electrical synapses. Spontaneous spiking was often synchronized in pairs of electrically coupled neurons, and the degree of this synchrony could be predicted from the magnitude of coupling. In wild-type mice, as in rats, the SCN contained electrical synapses, but electrical synapses were absent in connexin36-knockout mice. The knockout mice also showed dampened circadian activity rhythms and a delayed onset of activity during transition to constant darkness. We suggest that electrical synapses in the SCN help to synchronize its spiking activity, and that such synchrony is necessary for normal circadian behavior.

Interaction between an electronic and a biological circuit has been investigated for a pair of electrically connected nonlinear oscillators, with a spontaneously oscillating olivary neuron as the single-cell biological element. By varying the coupling strength between the oscillators, we observe a range of behaviors predicted by model calculations, including a reversible low-energy dissipation "amplitude death" where the oscillations in the coupled system cease entirely.

The inhibitory neurons of the thalamic reticular nucleus (TRN) contribute to the generation of widespread oscillations in the thalamocortical system. Some TRN neurons are interconnected by electrical synapses, and here we tested the possibility that electrical synapses mediate rhythmic synchrony in juvenile rats. Both the incidence and strength of electrical coupling between pairs of TRN neurons were a steep function of intersomatic distance, and coupling was absent at distances >40 microm. Presynaptic spike bursts evoked much larger electrical postsynaptic potentials than did single presynaptic spikes. Activation of metabotropic glutamate receptors (mGluRs) with a bath-applied agonist or an endogenous ligand released during tetanic stimulation induced robust rhythms of the subthreshold membrane potential, with a mean frequency of approximately 10 Hz. In the absence of fast chemical synaptic transmission, subthreshold rhythms and the action potentials that they evoked were well synchronized between closely spaced, electrically coupled pairs; rhythms in noncoupled cells were not synchronized. The results suggest that electrical synapses can coordinate spindle-frequency rhythms among small clusters of mGluR-activated TRN cells.

Many neurons in the mammalian central nervous system communicate through electrical synapses, defined here as gap junction-mediated connections. Electrical synapses are reciprocal pathways for ionic current and small organic molecules. They are often strong enough to mediate close synchronization of subthreshold and spiking activity among clusters of neurons. The most thoroughly studied electrical synapses occur between excitatory projection neurons of the inferior olivary nucleus and between inhibitory interneurons of the neocortex, hippocampus, and thalamus. All these synapses require the gap junction protein connexin36 (Cx36) for robust electrical coupling. Cx36 appears to interconnect neurons exclusively, and it is expressed widely along the mammalian neuraxis, implying that there are undiscovered electrical synapses throughout the central nervous system. Some central neurons may be electrically coupled by other connexin types or by pannexins, a newly described family of gap junction proteins. Electrical synapses are a ubiquitous yet underappreciated feature of neural circuits in the mammalian brain.

Neurons of the inferior olivary nucleus (IO) form the climbing fibers that excite Purkinje cells of the cerebellar cortex. IO neurons are electrically coupled through gap junctions, and they generate synchronous, subthreshold oscillations of membrane potential at approximately 5-10 Hz. Experimental and theoretical studies have suggested that both the rhythmicity and synchrony of IO neurons require electrical coupling. We recorded from pairs of IO neurons in slices of mouse brainstem in vitro. Most pairs of neurons from wild-type (WT) mice were electrically coupled, but coupling was rare and weak between neurons of knock-out (KO) mice for connexin36, a neuronal gap junction protein. IO cells in both WT and KO mice generated rhythmic membrane fluctuations of similar frequency and amplitude. Oscillations in neighboring pairs of WT neurons were strongly synchronized, whereas the oscillations of KO pairs were uncorrelated. Spontaneous oscillations in KO neurons were not blocked by tetrodotoxin. Spontaneously oscillating neurons of both WT and KO mice generated occasional action potentials in phase with their membrane rhythms, but only the action potentials of WT neuron pairs were synchronous. Harmaline, a beta-carboline derivative thought to induce tremor by facilitating rhythmogenesis in the IO, was injected systemically into WT and KO mice. Harmaline-induced tremors were robust and indistinguishable in the two genotypes, suggesting that gap junction-mediated synchrony does not play a role in harmaline-induced tremor. We conclude that electrical coupling is not necessary for the generation of spontaneous subthreshold oscillations in single IO neurons, but that coupling can serve to synchronize rhythmic activity among IO neurons.

Neurons of the thalamic reticular nucleus (TRN) provide inhibitory input to thalamic relay cells and generate synchronized activity during sleep and seizures. It is widely assumed that TRN cells interact only via chemical synaptic connections. However, we show that many neighboring pairs of TRN neurons in rats and mice are electrically coupled. In paired-cell recordings, electrical synapses were able to mediate close correlations between action potentials when the coupling was strong; they could modulate burst-firing states even when the coupling strength was more modest. Electrical synapses between TRN neurons were absent in mice with a null mutation for the connexin36 (Cx36) gene. Surprisingly, inhibitory chemical synaptic connections between pairs of neurons were not observed, although strong extracellular stimuli could evoke inhibition in single TRN neurons. We conclude that Cx36-dependent gap junctions play an important role in the regulation of neural firing patterns within the TRN. When combined with recent observations from the cerebral cortex, our results imply that electrical synapses are a common mechanism for generating synchrony within networks of inhibitory neurons in the mammalian forebrain.