Electrical synapse asymmetry results from, and masks, neuronal heterogeneity

Electrical synapses couple inhibitory neurons across the brain, underlying a variety of functions that are modifiable by activity. Despite recent advances, many basic functions and contributions of electrical synapses within neural circuitry remain underappreciated. Among these is the source and impact of electrical synapse asymmetry. Using multi-compartmental models of neurons coupled through dendritic electrical synapses, we investigated intrinsic factors that contribute to synaptic asymmetry and that result in modulation of spike time 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, true synapse asymmetry can be masked by each of these properties. Furthermore, we show that asymmetry alters the 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. These simulations illustrate that causes of asymmetry are multifactorial, may not be apparent in somatic measurements of electrical coupling, influence dendritic processing, and produce a variety of outcomes on spike timing of coupled cells. Our findings highlight aspects of electrical synapses that should be considered in experimental demonstrations of coupling, and when assembling networks containing electrical synapses.

NMDA receptors enhance the fidelity of synaptic integration

Excitatory synaptic transmission in many neurons is mediated by two co-expressed ionotropic glutamate receptor subtypes, AMPA and NMDA receptors, that differ in their kinetics, ion-selectivity, and voltage-sensitivity. AMPA receptors have fast kinetics and are voltage-insensitive, while NMDA receptors have slower kinetics and increased conductance at depolarized membrane potentials. Here we report that the voltage-dependency and kinetics of NMDA receptors act synergistically to stabilize synaptic integration of excitatory postsynaptic potentials (EPSPs) across spatial and voltage domains. Simulations of synaptic integration in simplified and morphologically realistic dendritic trees revealed that the combined presence of AMPA and NMDA conductances reduces the variability of somatic responses to spatiotemporal patterns of excitatory synaptic input presented at different initial membrane potentials and/or in different dendritic domains. This moderating effect of the NMDA conductance on synaptic integration was robust across a wide range of AMPA-to-NMDA ratios, and results from synergistic interaction of NMDA kinetics (which reduces variability across membrane potential) and voltage-dependence (which favors stabilization across dendritic location). When combined with AMPA conductance, the NMDA conductance balances voltage- and impedance-dependent changes in synaptic driving force, and distance-dependent attenuation of synaptic potentials arriving at the axon, to increase the fidelity of synaptic integration and EPSP-spike coupling across neuron state (i.e., initial membrane potential) and dendritic location of synaptic input. Thus, synaptic NMDA receptors convey advantages for synaptic integration that are independent of, but fully compatible with, their importance for coincidence detection and synaptic plasticity.Significance StatementGlutamate is an excitatory neurotransmitter that, at many synapses, gates two coexpressed receptor subtypes (AMPA and NMDA receptors). Computational simulations reveal that the combined synaptic presence of AMPA and NMDA receptors reduces variability in synaptic integration in response to identical patterns of synaptic input delivered to different dendritic locations and/or at different initial membrane potentials. This results from synergistic interaction of the slower kinetics and voltage-dependence of NMDA receptors, which combine to enhance synaptic currents when synaptic driving forces are otherwise reduced (e.g., at depolarized membrane potentials or in distal, high-impedance dendrites). By stabilizing synaptic integration across dendritic location and initial membrane potential, NMDA receptors provide advantages independent of, but fully compatible with, their well-known contribution to synaptic plasticity.

Regulation of AMPA and NMDA receptor-mediated EPSPs in dendritic trees of thalamocortical cells

Two main excitatory synapses are formed at the dendritic arbor of first-order nuclei thalamocortical (TC) neurons. Ascending sensory axons primarily establish contacts at large proximal dendrites, whereas descending corticothalamic fibers form synapses on thin distal dendrites. With the use of a multicomparment computational model based on fully reconstructed TC neurons from the ventroposterolateral nucleus of the cat, we compared local responses at the site of stimulation as well as somatic responses induced by both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and N-methyl-d-aspartate receptor (NMDAR)-mediated currents. We found that AMPAR-mediated responses, when synapses were located at proximal dendrites, induced a larger depolarization at the level of soma, whereas NMDAR-mediated responses were more efficient for synapses located at distal dendrites. The voltage transfer and transfer impedance were higher for NMDAR than for AMPAR activation at any location. For both types of synaptic current and for both input locations at the dendritic arbor, somatic responses were characterized by a low variability despite the large variability found in local responses in dendrites. The large neurons had overall smaller somatic responses than small neurons, but this relation was not found in local dendritic responses. We conclude that in TC cells, the dendritic location of small synaptic inputs does not play a major role in the amplitude of a somatic response, but the size of the neuron does. The variability of response amplitude between cells was much larger than the variability within cells. This suggests possible functional segregation of TC neurons of different size.

Frequency Selectivity Emerging from Spike-Timing-Dependent Plasticity

Periodic neuronal activity has been observed in various areas of the brain, from lower sensory to higher cortical levels. Specific frequency components contained in this periodic activity can be identified by a neuronal circuit that behaves as a bandpass filter with given preferred frequency, or best modulation frequency (BMF). For BMFs typically ranging from 10 to 200 Hz, a plausible and minimal configuration consists of a single neuron with adjusted excitatory and inhibitory synaptic connections. The emergence, however, of such a neuronal circuitry is still unclear. In this letter, we demonstrate how spike-timing-dependent plasticity (STDP) can give rise to frequency-dependent learning, thus leading to an input selectivity that enables frequency identification. We use an in-depth mathematical analysis of the learning dynamics in a population of plastic inhibitory connections. These provide inhomogeneous postsynaptic responses that depend on their dendritic location. We find that synaptic delays play a crucial role in organizing the weight specialization induced by STDP. Under suitable conditions on the synaptic delays and postsynaptic potentials (PSPs), the BMF of a neuron after learning can match the training frequency. In particular, proximal (distal) synapses with shorter (longer) dendritic delay and somatically measured PSP time constants respond better to higher (lower) frequencies. As a result, the neuron will respond maximally to any stimulating frequency (in a given range) with which it has been trained in an unsupervised manner. The model predicts that synapses responding to a given BMF form clusters on dendritic branches.