Structure and function of a neocortical synapse

Abstract

Thirty-four years since the small nervous system of the nematode C. elegans was manually reconstructed in the electron microscope (EM) 1 , 'high-throughput' EM techniques now enable the dense reconstruction of neural circuits within increasingly large brain volumes at synaptic resolution [2][3][4][5][6] . As with C. elegans, however, a key limitation for inferring brain function from neuronal wiring diagrams is that it remains unknown how the structure of a synapse seen in EM relates to its physiological transmission strength. Here, we related structure and function of the same synapses to bridge this gap: we combined paired whole-cell recordings of synaptically connected pyramidal neurons in slices of mouse somatosensory cortex with correlated light microscopy and high-resolution EM of all putative synaptic contacts between the neurons. We discovered a linear relationship between synapse size (postsynaptic density area) and synapse strength (excitatory postsynaptic potential amplitude), which provides an experimental foundation for assigning the actual physiological weights to synaptic connections seen in the EM. Furthermore, quantal analysis revealed that the number of vesicle release sites exceeded the number of anatomical synapses formed by a connection by a factor of at least 2.6, which challenges the current understanding of synaptic release in neocortex and suggests that neocortical synapses operate with multivesicular release, like hippocampal synapses [7][8][9][10][11] . Thus, neocortical synapses are more complex computational devices and may modulate their strength more flexibly than previously thought, with the corollary that the canonical neocortical microcircuitry possesses significantly higher computational power than estimated by current models.

Distinct Synaptic Transfer Functions in Same-Type Photoreceptors

“…However, building a direct bridge between them remains difficult. This difficulty is part related to the absence of a direct experimental link between our EM- and 2P-datasets, which we did not attempt in view of its extreme technical challenges (Holler et al, 2021) that to our knowledge have not been overcome for any ribbon synapse. Moreover, there is often more than one possible interpretation between a finding from EM and its functional consequence.…”

Distinct synaptic transfer functions in same-type photoreceptors

“…This difficulty is part related to the absence of a direct experimental link between our EM-and 2P-datasets, which we did not attempt in view of its extreme technical challenges (Holler et al, 2021) that to our knowledge have not been overcome for any ribbon synapse. Moreover, there is often more than one possible interpretation between a finding from EM and its functional consequence.…”

The Impact of Neuron Morphology on Cortical Network Architecture

“…Moreover, a subset of these axonal branches formed clusters of synapses by connecting to several close-by spines along the same dendrite (see also ( 13 )). At cellular scales, sparse reconstructions showed that axo-dendritic proximity is insufficient to account for the patterns of synaptic connections ( 14 ), or for differences in connection probabilities that reflect the neurons’ cell types ( 11 ). Because they are inconsistent with Peters’ Rule, such observations are considered to reflect wiring principles that are independent of the morphological properties of neurons.…”