Properties of networks formed by electrical synapses in the mamalian brain

Abstract

Gap junction-mediated electrical synapses can form networks of coupled neurons and also influence the synchronization of neuronal activity. Our understanding of electrical synapses remains limited, though, even as experimental evidence increasingly demonstrates their prevalence in the mammalian brain. This work investigates the properties of networks formed by electrical synapses by (1) characterizing electrical coupling in the trigeminal mesencephalic (MesV) nucleus, and by (2) describing the qualitative aspects of coupling in the extensively coupled network of neurons in the inferior olive (IO). In the MesV nucleus, primary sensory afferent neurons relay proprioceptive signals associated with jaw movements. This nucleus provided early evidence of mammalian electrical synapses but the detailed properties of electrical coupling have remained unknown. Using electrophysiology, tracer coupling, and immunohistochemistry techniques we determined that the MesV nucleus is organized in mostly pairs of coupled somata with electrical transmission supported by a small fraction of available gap junction channels, and where coupling interacts synergically with specific membrane conductances to promote synchronization of these neurons. Next, the inferior olive (IO) provides climbing fibers innervating the cerebellar cortex and is likely involved in motor movements and coordination. IO neurons are interconnected exclusively by gap junctions and coupling underlies the transient formation of functional IO compartments. Most functional considerations assume a network of permanently and homogeneously coupled IO neurons. However, our results indicate that IO coupling is highly variable: individual IO neurons can be coupled to variable numbers of neighboring neurons, and a single neuron may be coupled at remarkably different strengths with each of its partners. Also, freeze-fracture analysis of IO glomeruli revealed glutamatergic postsynaptic densities in close proximity to Cx36-containing gap junctions. Based on similarities with goldfish mixed synapses we speculate that, rather than hardwired, variations in coupling could result from glomerulus-specific long-term modulation of gap junctions. This striking coupling heterogeneity might act to influence the synchronization of IO neurons and add complexity to olivary networks. In summary, this work shows that electrical synapses can form a diversity of network arrangements where heterogeneity of coupling and interactions with cellular properties constitute important functional determinants of networks of electrically coupled neurons.