Human pyramidal neurons at the center of brain diversity
Authors:   , Mertens Eline Jasmijn 
Published: January 2025

Chapter 2: Cellular properties of human hippocampal CA1 neurons.
This chapter investigates the structural and functional properties of human hippocampal CA1 neurons, highlighting adaptations that support advanced cognitive processes and how these differ from mice. Human CA1 neurons are significantly larger and more complex than previously understood, with dendritic lengths reaching up to a millimeter. These larger neurons possess a greater number of oblique dendrites, which function as independent processing units, thereby substantially enhancing memory capacity. Additionally, nearly all human CA1 neurons exhibit a resonance frequency closely aligned with low theta rhythms, critical for memory encoding and spatial navigation.

In contrast, mouse CA1 neurons are structurally simpler and display resonance less frequently, with a less precise alignment to theta rhythms. This suggests that mouse neurons are adapted for survival-related tasks rather than complex cognitive functions. Furthermore, the memory capacity of human CA1 neurons was found to be 11 times higher, a difference largely attributed to the role of oblique dendrites in humans. These findings provide strong evidence of species-specific adaptations in hippocampal neurons, which underpin humans' advanced cognitive abilities.

Chapter 3: Synaptic communication in human pyramidal neurons compared to rodents.

This chapter examines how synaptic communication in human pyramidal neurons of the cortex differs from rodents. Human neurons exhibit synaptic conductance and voltage changes three times greater than those of mice, resulting in significantly stronger and more reliable synaptic transmission. Connected human neurons respond nearly 100% of the time, compared to a 25% failure rate observed in rodents. Pharmacological studies confirmed that NMDA receptors play a critical role in this enhanced synaptic strength. Blocking NMDA receptors significantly reduced excitatory postsynaptic potentials (EPSPs) in human neurons, while the effect was less pronounced in rodents. NMDA receptor activation prolongs EPSPs and supports long-term potentiation (LTP), a fundamental mechanism for learning and memory.

Interestingly, the enhanced synaptic strength and reliability are not due to a higher number of synapses per connection, as both species have an average of five synapses per pair. Instead, human neurons exhibit larger presynaptic active zones and postsynaptic densities, which enhance neurotransmitter release and receptor binding. Additionally, the human cortex contains approximately three times more total synapses than the rodent cortex, facilitating more long-range cortical connections. These features support complex and integrated neural networks that underlie human-specific cognitive functions. These adaptations illustrate how the human brain has evolved to manage more sophisticated cognitive tasks than the rodent brain.

Chapter 4: Regional variability in morpho-Electric properties of human neocortical pyramidal neurons.
This chapter explores the regional variability of superficial and deep pyramidal neurons in layers 2 and 3 (L2/L3) of the human neocortex. Superficial neurons, primarily involved in feedback processing, and deep neurons, responsible for feedforward projections, exhibit distinct regional patterns along the rostro-caudal axis.
Superficial L2/L3 neurons show a gradient where structural complexity decreases and excitability increases from the frontal to the occipital lobe. This suggests that neurons in the frontal cortex are optimized for higher-order cognitive functions, such as decision-making and working memory. Conversely, neurons in the occipital cortex, with higher excitability, are better suited for rapid sensory information processing. Deep L2/L3 neurons exhibit less pronounced structural and excitability gradients but show a marked increase in HCN channel activity, indicated by a higher sag ratio, along the same axis. This suggests that deep neurons play a key role in modulating cortical excitability and supporting long-distance communication between cortical regions.
These findings demonstrate that superficial and deep L2/L3 pyramidal neurons follow distinct specialization gradients. The regional variability of these neurons enables the human neocortex to meet diverse computational demands across different cortical areas.