Axonal myelination is a conserved feature of PVFS interneurons across mammals. Kole et al. (2022) showed that basket cells possess myelinated axons with mitochondria clustered within myelinated segments in rodent neocortex, supporting the energetic demands of rapid signaling. Myelination reduces effective axonal membrane capacitance, approximately 0.05 μF/cm² for a 10-fold myelin wrap, thereby increasing conduction velocity and decreasing the energetic cost of action potential propagation (Castelfranco and Hartline, 2015).

PVFS interneuron axons are more frequently and more extensively myelinated in humans (Micheva et al., 2018; Stedehouder et al., 2019; Benamer et al., 2020). In the mouse neocortex, roughly 25–40% of PV interneurons have detectable myelination on parts of their axons. In the human neocortex, this proportion rises to 60–80%, depending on the cortical area and age. Both human and rodent PV interneurons display proximal axonal myelination, typically beginning near the soma, distal to the AIS. Human PVFSs exhibit greater overall myelination, with longer total myelinated lengths and more internodes (Stedehouder et al., 2017).

In addition, the myelin sheath tends to be thicker in humans relative to axon diameter. The g-ratio (axon diameter/fiber diameter) is smaller in humans (~0.6–0.7) than in rodents (~0.75–0.8) for PV interneurons, indicating thicker relative myelin. The g-ratio optimizes speed. Empirically, conduction velocity is maximal around g ≈ 0.6.

The primary benefit of thicker myelin is in active saltatory conduction of the action potential along the myelinated axon from one node to the next. A thicker myelin sheet reduces cell capacitance per surface area in the axon. In addition, a thicker myelin sheet increases transmembrane resistance, since it acts as a high-resistance electrical insulator by decreasing current leakage across the membrane. Each additional layer of myelin roughly doubles the effective membrane thickness, thereby reducing membrane capacitance and increasing membrane resistance exponentially. These changes increase the membrane length constant that determines how far along an axon a passive voltage change can spread before it decays significantly. Voltage changes spread farther along the axon before decaying, and there is less voltage attenuation between nodes of Ranvier, where action potentials are generated (Table 1).

Increased myelination in human cells likely reflects an adaptation to larger neuronal size and longer conduction paths in the human cortex. By lowering axonal capacitance and leak conductance, myelination enhances propagation speed and reduces energy expenditure, contributing to the metabolic efficiency of fast and precise inhibition in large cortical networks (Hartline and Colman, 2007; Fields, 2015; Benamer et al., 2020). However, if myelin is too thick, the capacitance gain saturates, and metabolic cost increases (Table 2).

Perineuronal nets (PNNs) are specialized extracellular matrix structures that envelop the soma and proximal dendrites of PVFS interneurons in both rodents and humans. These structures mainly contain chondroitin sulfate proteoglycans (CSPGs), hyaluronan, tenascin-R, and link proteins (see Morphett et al., 2024 for review). Yet, the PNN is more than just an extracellular scaffold: it strongly influences metabolic efficiency, ion homeostasis, and electrical signaling (for a review of PNN role in metabolism see Zhang et al., 2024).

PNN can save metabolic energy indirectly by reducing ion leak and buffering extracellular ions. First, the dense extracellular matrix limits extracellular diffusion and movement of K⁺ and Na⁺ ions near the soma, helping maintain local ionic stability, which reduces the need for constant active pumping (via Na⁺/K⁺-ATPase) - a major ATP consumer - to restore gradients after each spike. By restricting ion and water diffusion near the membrane, PNNs can lower the effective membrane capacitance of fast-spiking neurons, thereby facilitating electrical rapidity by shortening the soma time constant for membrane potential changes. In addition, PNN can reduce energy requirements by restricting cell volume changes (Tewari et al., 2018). Second, dense PNN has strengthened the electrostatic stabilization effect where negatively charged glycosaminoglycan chains in the PNN create a fixed negative potential that may help stabilize extracellular charge distribution and buffer cations, indirectly reducing leak currents and ionic perturbations during fast firing. Third, by anchoring perisomatic inhibitory synapses PNN stabilizes synaptic connections (Bosiacki et al., 2019; Fawcett et al., 2019; Auer et al., 2025). Experimental degradation of PNNs in rodents reduces firing rates and electrical gain of PVFS cells, leading to instability and impaired rhythmic activity at the neuronal network level (Hanssen et al., 2023) (Table 3).

Although the general morphology of PNNs is conserved across species, molecular composition and density appear to differ. Human and other primate PNNs show higher molecular density and more dense organization, whereas rodent PNNs are simpler and less dense (Mcgillis, 2018; Belliveau et al., 2024; da Silva et al., 2024). These molecular and structural differences may influence the biophysical properties of PNNs, and the more dense and molecularly rich PNN in humans may contribute to enhanced energy-saving function by enhanced ion buffering (Chaunsali et al., 2021) and protection against oxidate stress in human PVFS neurons (Morawski et al., 2004).

PNN also affects electrical signaling speed indirectly. Because the PNN is extracellular, it does not directly change the membrane’s capacitance or resistance. However, it can enhance the electrical signaling by stabilizing the extracellular ionic and electric field environment, which in turn affects how currents flow during synaptic and action potential activity. By reducing ion diffusion at the extracellular surface of the membrane, PNN helps maintain low extracellular K⁺ and high Na + during rapid firing. This supports consistent spike amplitude and timing, effectively increasing the temporal precision of firing.

Human PVFS neurons exhibit higher input resistance than their rodent counterparts (Szegedi et al., 2016; Szegedi et al., 2023; Wilbers et al., 2023; Furdan et al., 2025), likely due to species-specific differences in leak channel density and transmembrane ionic conductances. Leak channels mediate passive ion fluxes that mainly determine the resting membrane potential (Gadsby, 2009) and generate an energetic cost, as ionic gradients must be continuously restored by Na⁺/K⁺-ATPases. In neurons with a larger membrane surface area, high leak conductance increases ATP demand. Thus, the higher input resistance of human PV interneurons likely reflects a reduction in passive ion leakage, lowering baseline ATP demand. The increased input resistance allows the resting membrane potential to be maintained and the generation of membrane potential changes, including synaptic excitation and inhibition and action potentials, with smaller ion currents, thereby reducing the energy cost of maintaining ionic gradients (Table 4).

On the other hand, higher resistance also slows the time course of membrane potential kinetics, potentially compromising temporal precision (Szegedi et al., 2023). To compensate, human PVFS neurons exhibit additional adaptations. One is the somatic expression of hyperpolarization-activated cyclic nucleotide–gated (HCN) channels, which facilitate kinetics of membrane potential changes in soma to shorten the action potential generation delay (Szegedi et al., 2023). In contrast, rodent PVFS neurons express HCN channels primarily on their axons (Roth and Hu, 2020), showing that while HCN channel expression is evolutionarily conserved, its subcellular localization has shifted in humans. This somatic localization likely enhances the rapidity to transform excitatory synaptic inputs to an AP (Kalmbach et al., 2018; Szegedi et al., 2023). HCN channels are strongly modulated by intracellular factors such as pH or Ca2+ (Combe and Gasparini, 2021), which make the electrical properties of the human PVFS cell soma a substrate for plasticity regulations.

In addition to HCN channels, inwardly rectifying potassium (Kir) channels also help regulate PVFS membrane resistance and excitability (Furdan et al., 2025). Human PVFSs achieve comparable input resistance regulation with lower Kir conductance than mouse cells, owing to their higher baseline membrane resistance. This reduced Kir activity for equal excitability regulation represents another energy-conserving adaptation, minimizing unnecessary ion flow and ATP requirements through voltage-activated ion channels (Furdan et al., 2025).

The electrotonic transduction of membrane potential changes is less efficient in human neurons with longer dendritic elongations. Human PVFSs in the supragranular layer, which is a particularly proliferated neocortical layer in humans compared to other mammals, have structural specializations to compensate for this (Wilbers et al., 2023). A recent study shows that human PVFSs have a simplified structure of large dendrites compared to those in rats, with a smaller number of branching points. This structural specialization improves the electrotonic propagation of membrane potential changes over longer dendritic distances, since the simplified dendritic structure with fewer branching points results in less signal attenuation. Long dendrites suffer greater voltage attenuation and temporal dispersion of signals reaching the soma. In addition, from the point of view of the main dendrite, each branch behaves as a current sink where the axial current divides, causing attenuation and slowdown of the forward propagation of voltage along the main dendrite (Wilbers et al., 2023). Signals decay faster and arrive with smaller amplitude at the soma. Therefore, PVFS interneurons in the supragranular layer of human cortex may have evolved with a simplified dendritic tree, because less division of current enables less voltage attenuation along the main shaft. The shorter total electrotonic path allows faster and stronger signal transmission from distal to proximal sites. This is particularly advantageous for fast-spiking interneurons that rely on precise temporal signaling. However, the reduced dendritic tree comes at a cost of reduced synaptic integration capacity but fewer total synapses. However, the human neocortex compensates this functional trade-off between the electrical efficiency of PVFS neurons and the network computational capacity by an increased proportional number of interneurons compared to pyramidal cells (see, e.g., Kanari et al., 2025).

In addition, fewer branches reduce metabolic cost. There is less maintenance of ion gradients across the total membrane surface area (via Na⁺/K⁺ ATPase), less metabolic maintenance of cytoplasmic and membrane-bound processes in distal locations from the soma for structural (cytoskeleton) and transport support, and reduced biosynthetic costs for ion channels and receptors (Attwell and Laughlin, 2001; Karbowski, 2007) (Table 5).

Compared with rodents, human parvalbumin-expressing fast-spiking interneurons (PVFSs) exhibit a lower action potential (AP) threshold at the axon initial segment (AIS) in response to somatic excitatory inputs. Together with the higher input resistance of human interneurons, this reduced AP threshold decreases the amount of depolarizing current—and therefore transmembrane ion flux—required to generate an output spike. Both features are neuroeconomically advantageous, as they minimize energetic cost per signaling event.

The reduced AP threshold in human PVFSs arises from a marked depletion of Kv1-type potassium channels in the AIS (Bakos et al., 2025). Human PVFS neurons lack Kv1.1 channels entirely, show no detectable expression of the corresponding gene KCNA1, and express Kv1.2 channels at substantially lower levels in the AIS compared with rodents (Bakos et al., 2025). In the absence of this Kv1-mediated outward current, smaller depolarizations are sufficient to trigger regenerative Na⁺ channel activation and initiate an AP.

Consequently, baseline K⁺ efflux at rest and near threshold is reduced during spike initiation. The accompanying reduction in both Na⁺ and K⁺ transmembrane currents lowers the workload of the Na⁺/K⁺-ATPase required to restore ionic gradients after spiking. In addition, the absence of Kv1 channels reduces the biosynthetic and maintenance costs associated with producing and trafficking these ion channels, further contributing to energetic efficiency in human PVFS interneurons.

Beyond energetic considerations, a lowered AP threshold also compensates for the slower membrane potential dynamics associated with the higher input resistance and larger somatic size of human interneurons. At the AIS, the critical transformation from excitatory postsynaptic potential (EPSP) to AP depends on how rapidly the local membrane potential reaches the Na⁺ channel activation threshold. In an AIS with low Kv1 channel density, depolarizing current originating in the soma spreads more efficiently into the AIS, while the reduced outward K⁺ conductance allows the local membrane potential to rise more steeply.

By diminishing subthreshold K⁺ “drag,” the AIS shortens the latency between EPSP onset and spike initiation. Thus, the lowered AP threshold in human PVFSs compensates for slower membrane charging, ensuring rapid and reliable action potential generation in response to excitatory synaptic input (Wilbers et al., 2023; Bakos et al., 2025) (Table 6).

Human PVFSs have lower (more depolarized) resting membrane potential (Em) than their rodent counterparts (Szegedi et al., 2023), which, together with the increased input resistance and the lowered AP threshold in the cells, synergistically works to reduce the amount of excitatory current and transmembrane ion current to generate AP by excitatory synaptic inputs. This is neuroeconomical because neuronal energy consumption primarily stems from restoring electrochemical gradients through ATP-dependent ion pumps following electrical activity (Harris et al., 2012; Muangkram et al., 2023). The Na⁺/K⁺ pump accounts for up to 50% of neuronal ATP use (Attwell and Laughlin, 2001; Meyer et al., 2022).

Pump activity increases with more negative resting membrane potential, as its generation and maintenance require greater electrical work to expel Na⁺ and intake K⁺ (Gadsby et al., 1985; Hansen et al., 2002). A more depolarized resting membrane potential, as reported in human FSPV neurons (Szegedi et al., 2023; Wilbers et al., 2023), is likely to reduce this energetic burden, thus being neuroeconomical by lowering ATP demand while maintaining high excitability in human PVFSs. The depolarized Em is likely to stem from fewer open K⁺ channels, causing reduced passive K⁺ efflux, in resting conditions (for a review of two-pore-domain K + channels, or leak channels, see Lesage and Lazdunski, 2000). This also means less biosynthetic burden (Table 7).

Mitochondria provide the ATP required for neuronal signaling via oxidative phosphorylation (Mattson et al., 2008). There is some evidence indicating species differences in mitochondrial structure, metabolism, and distribution between human and rodent neurons, which will be discussed in more detail below.

Comparative analyses indicate that mitochondria in the human cerebral cortex differ molecularly and functionally from those in rodents, reflecting species-specific adaptations in bioenergetics (Westi et al., 2022). These differences suggest a distinct “mitotype” in humans that supports the energetic demands of large, high-performance cortical networks (Pontzer et al., 2016). Although differences in overall brain metabolism—such as substrate usage, coupling efficiency, and mitochondrial proteome—have been reported between species, no cell-type-specific studies have yet examined these features in parvalbumin-expressing interneurons. To date, there are no direct comparative data on the number, density, or subcellular distribution of mitochondria in human versus rodent PV interneurons (Table 8).

In the human cortex, mitochondria display a high degree of regional and cellular specialization that presumably aligns with local computational and metabolic demands. The distribution of mitotypes follows a phylogenetic gradient, meaning that mitochondrial adaptations co-evolved with the expansion of higher-order association cortices in primate evolution (Mosharov et al., 2025). In isolated preparations, human cortical mitochondria exhibit lower oxygen consumption but equal or greater ATP output compared with mouse mitochondria, indicating more efficient oxidative phosphorylation coupling (Jeffreys and Craig, 1974). In parallel, transcriptomic and proteomic analyses reveal divergent gene expression and protein synthesis patterns between human and rodent mitochondria (for a review on cardiac cells, see Alibrandi and Lionetti, 2025), further emphasizing functional specialization at the molecular level.

Human and mouse neurons differ in mitochondrial development and metabolic activity, thereby affecting neuronal maturation. In humans, cortical neurons exhibit slower mitochondrial growth and lower oxidative metabolism, leading to a longer developmental timeline. In contrast, mouse neurons undergo faster mitochondrial maturation and generate energy more rapidly through oxidative phosphorylation (Iwata et al., 2023).

Mitotypes vary not only between species but also across neuronal classes (see Kuznetsov and Margreiter, 2009 for a review) (Fecher et al., 2019) indicating cell–type–specific energetic specializations. Even within a single neuron, the mitochondrial population is heterogeneous: axonal and dendritic mitochondria display divergent genetic and functional characteristics (Hirabayashi et al., 2024), as shown in pyramidal cells. It is therefore reasonable to assume that PVFS interneurons harbor mitochondria adapted to their exceptionally high energetic and temporal demands.

Parvalbumin basket cell myelination accumulates axonal mitochondria in internodes. A recent study in a mouse model shows that in PV-positive basket cell axons, myelinated segments show a higher mitochondrial density than unmyelinated segments within the same axon. Regarding that human PVFS cell axons are more extensively myelinated; they may also be richer in mitochondria. Given the larger size and longer axonal/dendritic distances of human cortical neurons, one might predict that human PV interneurons would have increased mitochondrial content or different localization (e.g., more mitochondria in distal processes) or enhanced coupling efficiency — but this remains to be empirically verified.

However, across many mammalian species, the density of mitochondria per unit area of neuropil in the cortex appears conserved, and mitochondria density does not scale with brain size, thus large- vs. small-brained mammals have similar mitochondria densities (Karl et al., 2024). This suggests an evolutionary constraint on mitochondrial number and density in the cortical neuropil, and also indicates that brain enlargement in mammals is accompanied by an increase in the number of mitochondria per neuron. To date, there is no direct comparison of mitochondrial number, density, or subcellular localization specifically in human PV interneurons compared to rodent PV interneurons.

Excitatory synapses from pyramidal neurons onto PV basket cells are more efficient in humans than in rodents, in terms of generating action potential discharge (Molnar et al., 2008; Komlosi et al., 2012; Szegedi et al., 2016; Szegedi et al., 2017). Human connections contain approximately four times more functional release sites—around 6.2 per active zone compared with 1.6 in rats (Molnar et al., 2016). Electron microscopy further shows that the synapses’ active zones have approximately four docked vesicles in humans, compared to one in rodents. This enables a single presynaptic spike to release more neurotransmitter and elicit a larger excitatory postsynaptic current, sufficient to recruit local interneurons synchronously (Molnar et al., 2008; Szegedi et al., 2016).

In rodents, excitatory inputs onto basket cells are more numerous (Veres et al., 2017). The higher frequency of miniature EPSPs reported in rats compared with monkeys corresponds to denser excitatory innervation (Povysheva et al., 2008). In contrast, primates achieve comparable or greater postsynaptic efficacy with fewer but stronger synapses—a distinct energy-efficient strategy.

Cellular reconstruction analysis reveals that human basket cells receive more GABAergic synapses on their somata and proximal dendrites than those of mice (Rebollo et al., 2025). The high number of inhibitory synapses is likely to reflect the increased number of interneurons and cell density in the human cortex compared to the rodent cortex, as evidenced by the similarity in the number of autaptic GABAergic synapses to human and mouse PV immunopositive basket cells (Szegedi et al., 2020). However, in smaller GABAA-receptor activation is needed in human PVFSs for an equal level of inhibition, measured as a relative drop of the cell input resistance by GABAAR-mediated synaptic conductance (Szegedi et al., 2020)-because of the higher starting resting input resistance of the human cells (Szegedi et al., 2023).

Human PVFSs may also produce faster and stronger inhibitory outputs compared with rodents (Wilbers et al., 2023). Individual human basket cells form more inhibitory boutons per postsynaptic pyramidal neuron than those of rodents (Karube et al., 2004; Kubota et al., 2016). The increased number of boutons per target improves transmission reliability, allowing efficient control of pyramidal neuron firing with fewer presynaptic spikes (Table 9).