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Increased Electrical Compartmentalization Observed in Human Cortical Neurons

Key findings

  • The longer length of dendrites in human cortical neurons compared to animal neurons results in increased electrical compartmentalization
  • The greater compartmentalization is due to lower ion channel densities
  • Compartmentalization alters the input–output properties of human neurons, potentially suggesting a role for human dendrites in cortical computation

Dendrites in human neurons are longer than those in rodents and primates, which might help individual neurons compartmentalize synaptic integration and information processing. However, compartmentalization also relies on membrane properties and active conductances, so it's been unclear how the larger size of human neurons affects synaptic integration.

Sydney S. Cash, MD, PhD, assistant in neurology at Massachusetts General Hospital, and Mark Harnett, PhD, at MIT, and colleagues have determined ex vivo that human dendrites exhibit increased electrical compartmentalization compared to rat dendrites due to lower ion channel densities. In Cell, they report that the greater compartmentalization alters the input-output properties of neurons and may give them a richer computational repertoire.

Reduced Burst Firing in Human Neurons

First, the team obtained layer 5 (L5) pyramidal neurons from human temporal lobe tissue and comparable neurons from rats. In response to electrical current, most rat neurons exhibited high-frequency bursts of action potentials, but few human neurons did.

Increased Input in Human Dendrites

Rodent L5 apical dendrites are known to possess high densities of ion channels, including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. The researchers used hyperpolarizing current injections to map the properties of apical dendrites at various distances from the soma.

In both rat and human dendrites, there was an increase in voltage sag as a function of distance, but the distance-dependent profile in human dendrites extended across their length. Intriguingly, input resistance was dramatically larger in distal human dendrites than in distal rat dendrites.

The researchers note that HCN channels are apparently enriched in distal human dendrites, but the higher resistance suggests that human dendrites possess fewer open conductances at rest.

Enhanced Electrical Compartmentalization in Human Neurons

Voltage spread toward the soma was comparable in rat and human dendrites. However, due to their increased length, human dendrites exhibited much more pronounced attenuation.

Rat distal dendrites had a much lower impedance than rat soma, and backward attenuation was stronger than forward attenuation. In human neurons, the impedance profile was the opposite.

Using several types of experiments, the researchers determined that membrane capacitance was not lower in human neurons than in rat counterparts. Taken together, they say, the results demonstrate that both resistive and capacitive filtering are more pronounced in human neurons because of their increased length.

Compartmentalization Limits Dendritic Spikes and Somatic Bursts in Human Neurons

The researchers compared the active properties of human and rat dendrites after injecting current near the main bifurcation point in neurons. In rat neurons, the current triggered typically wide dendritic spikes coupled to somatic bursts. In human neurons, the dendritic spikes failed on their way to the soma. The spikes were weaker with reduced width and area, and distal spikes had slower onsets than those in rats.

The researchers believe that in human neurons, distal dendritic integration has limited influence on somatic output.

Rat and Human Dendrites Possess Similar Ion Channel Distributions

In considering what might explain the distinctive spike properties in human neurons, the researchers speculated that enhanced electrical segregation between the somatic and dendritic compartments might limit regenerative interactions between the two compartments. They tested this idea in rat neurons by dissociating dendritic spikes from somatic action potentials, thus mimicking the increased compartmentalization of human neurons.

Specifically, the researchers used a somatic voltage clamp to prevent the generation of somatic action potentials. That converted rat distal dendritic spikes into human spikes in terms of width, area and onset. The team then did the opposite experiment, clamping distal dendrites to prevent dendritic electrogenesis, and observed complete elimination of burst firing.

This novel approach suggests that the distinctive spike properties in human neurons represent weaker somato-dendritic coupling compared with rat neurons, not different complements of voltage-gated ion channels.

Stretched Ion Channel Distributions in Human Neurons

Even though ion channel distributions were similar in rat and human dendrites, the researchers believed the size difference suggested a redistribution of the conductances. To explore further, they extended their novel rat model to the length of a human neuron in two ways:

  • Stretching the apical dendrites, without affecting the number and distribution of ion channels, reproduced the reduced somato-dendritic coupling and distinctive spike properties of human neurons
  • Scaling the model, such that local ion channel densities were maintained but the total number of channels increased, failing to capture the limited coupling of human neurons

Therefore, the higher input resistance in human dendrites seems attributable to stretching—lower ionic channel densities—compared with rat neurons. Directly measuring dendritic conductances supported this proposition.

The Advantage of Long Dendrites

The increased electrotonic length of human dendrites seems counterintuitive. Distal inputs provide little excitation to the soma, so distal synaptic integration would incur significant metabolic costs without purpose.

But actually, electrical isolation may provide an evolutionary advantage, the researchers continue. Theoretical studies have suggested a role for dendrites in parallel processing and subsequent nonlinear transformations prior to integration at the axon. If the electrical structure of human dendrites results in additional compartments or more isolated compartments that are capable of nonlinear transformation, single neurons might have the sophistication of small computational networks.

Still, factors not studied yet, such as patterns of synaptic inputs and neuromodulatory control, might compensate for the increased length of human neurons. In vivo studies are necessary to show whether extreme compartmentalization in human dendrites is an enhancement of computational power—or a bug in need of correction.

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