Intrinsic Sources and Functional Impacts of Asymmetry at Electrical Synapses

Abstract

Electrical synapses couple inhibitory neurons across the brain, underlying a variety of functions that are modifiable by activity. Despite recent advances, many functions and contributions of electrical synapses within neural circuitry remain underappreciated. Among these are the sources and impacts of electrical synapse asymmetry. Using multi-compartmental models of neurons coupled through dendritic electrical synapses, we investigated intrinsic factors that contribute to effective synaptic asymmetry and that result in modulation of spike timing and synchrony between coupled cells. We show that electrical synapse location along a dendrite, input resistance, internal dendritic resistance, or directional conduction of the electrical synapse itself each alter asymmetry as measured by coupling between cell somas. Conversely, we note that asymmetrical gap junction conductance can be masked by each of these properties. Furthermore, we show that asymmetry modulates spiking timing and latency of coupled cells by up to tens of milliseconds, depending on direction of conduction or dendritic location of the electrical synapse. Coordination of rhythmic activity between two cells also depends on asymmetry. These simulations illustrate that causes of asymmetry are diverse, may not be apparent in somatic measurements of electrical coupling, influence dendritic processing, and produce a variety of outcomes on spiking and synchrony of coupled cells. Our findings highlight aspects of electrical synapses that should always be included in experimental demonstrations of coupling, and when assembling simulated networks containing electrical synapses. 3 SIGNIFICANCE STATEMENTAsymmetry, or unequal transmission of current between two coupled neurons, is a property of electrical synapses often noted but seldom explored. Here we show that multiple intrinsic factors can either produce, or mask, asymmetry. Spike timing and rhythmic synchrony are both affected by asymmetric connections between neurons. These results highlight important consequences of asymmetry that are likely to be recapitulated within coupled networks throughout the brain.

Neuropeptide Modulation Enables Biphasic Inter-network Coordination via a Dual-Network Neuron

“…Electrical synapses alone and in combination with chemical synapses can have surprising and complex effects on network outputs (Alcamí and Pereda, 2019; Connors, 2017; Marder et al, 2017; Vaughn and Haas, 2022). Rectification of electrical synapses occurs to different extents and can further add to the complexity of electrical synapse contributions, such as enabling coincidence detection and amplification of chemical synapses, and shaping network sensitivity to chemical synapses (Connors, 2017; Edwards et al, 1998; Gutierrez and Marder, 2013; Liu et al, 2017; Mendoza and Haas, 2022; Palacios-Prado et al, 2014; Rash et al, 2013; Vaughn and Haas, 2022).…”

“…Rectification of electrical synapses occurs to different extents and can further add to the complexity of electrical synapse contributions, such as enabling coincidence detection and amplification of chemical synapses, and shaping network sensitivity to chemical synapses (Connors, 2017;Edwards et al, 1998;Gutierrez and Marder, 2013;Liu et al, 2017;Mendoza and Haas, 2022;Palacios-Prado et al, 2014;Rash et al, 2013;Vaughn and Haas, 2022).…”

On the Diverse Functions of Electrical Synapses

“…Asymmetry could result from heterotypy of gap junction channels and plaques, where oligomerization or docking of different connexin or innexin proteins can asymmetrically pass current ( Bukauskas et al, 1995 ; Phelan et al, 2008 ; Rash et al, 2013 ), and differences in hemichannel scaffolding ( Marsh et al, 2017 ) could also contribute to the rectifying ability of electrical synapses. Even for homotypic gap junctions based on connexin36, which are largely voltage-independent ( Srinivas et al, 1999 ), differences between cell properties, such as input resistance or cable properties, create functional asymmetry for signals sent across the gap junction ( Mann-Metzer and Yarom, 1999 ; Veruki and Hartveit, 2002a ; Nadim and Golowasch, 2006 ; Alcami and Marty, 2013 ; Amsalem et al, 2016 ; Mendoza and Haas, 2022 ). Furthermore, those different sources of asymmetry can also compensate for or exacerbate genuine junctional asymmetry between electrical synapses ( Mendoza and Haas, 2022 ).…”

“…Even for homotypic gap junctions based on connexin36, which are largely voltage-independent ( Srinivas et al, 1999 ), differences between cell properties, such as input resistance or cable properties, create functional asymmetry for signals sent across the gap junction ( Mann-Metzer and Yarom, 1999 ; Veruki and Hartveit, 2002a ; Nadim and Golowasch, 2006 ; Alcami and Marty, 2013 ; Amsalem et al, 2016 ; Mendoza and Haas, 2022 ). Furthermore, those different sources of asymmetry can also compensate for or exacerbate genuine junctional asymmetry between electrical synapses ( Mendoza and Haas, 2022 ). For example, at the Mauthner mixed synapse, heterotypic asymmetrical gap junctions composed of connexin34.7 and connexin35 preferentially pass current from the Mauthner cell to the club endings.…”

“…For more moderate asymmetry, modeling results reveal an effect of asymmetry on detailed spike timing, even to the extent of reversing spike order in a coupled cells ( Sevetson and Haas, 2015 ), and controls the phase of synchronous rhythmic activity ( Mendoza and Haas, 2022 ). Modeling of larger networks shows that rectifying electrical synapses can improve the robustness of rhythmic activity ( Gutierrez et al, 2013 ).…”