Synaptic Organization of the Human Temporal Lobe Neocortex as Revealed by High-Resolution Transmission, Focused Ion Beam Scanning, and Electron Microscopic Tomography

Modern electron microscopy (EM) such as fine-scale transmission EM, focused ion beam scanning EM, and EM tomography have enormously improved our knowledge about the synaptic organization of the normal, developmental, and pathologically altered brain. In contrast to various animal species, comparably little is known about these structures in the human brain. Non-epileptic neocortical access tissue from epilepsy surgery was used to generate quantitative 3D models of synapses. Beside the overall geometry, the number, size, and shape of active zones and of the three functionally defined pools of synaptic vesicles representing morphological correlates for synaptic transmission and plasticity were quantified. EM tomography further allowed new insights in the morphological organization and size of the functionally defined readily releasable pool. Beside similarities, human synaptic boutons, although comparably small (approximately 5 µm), differed substantially in several structural parameters, such as the shape and size of active zones, which were on average 2 to 3-fold larger than in experimental animals. The total pool of synaptic vesicles exceeded that in experimental animals by approximately 2 to 3-fold, in particular the readily releasable and recycling pool by approximately 2 to 5-fold, although these pools seemed to be layer-specifically organized. Taken together, synaptic boutons in the human temporal lobe neocortex represent unique entities perfectly adapted to the “job” they have to fulfill in the circuitry in which they are embedded. Furthermore, the quantitative 3D models of synaptic boutons are useful to explain and even predict the functional properties of synaptic connections in the human neocortex.

Local and global dichotomic dysfunction in resting and evoked functional connectivity precedes tauopathy

Functional activity alterations are one of the earliest hallmarks of Alzheimer’s disease (AD), already detected prior to beta-amyloid plaque and tau-tangle accumulation. To reveal the physiological basis underpinning these changes at the onset of the pathology, we leveraged fMRI in the 3xTgAD mouse model for AD. Resting-state fMRI revealed functional connectivity loss within areas homologous to the human temporal lobe, particularly the entorhinal cortex. Optogenetic activation of the entorhinal cortex results, instead, in enhanced fMRI signal, thus denoting an increase in metabolic demand under load. This is corroborated by synaptic hyperexcitability in the highlighted projection targets, reported with electrophysiological recordings. Thus, 3xTgAD mice reveal a dichotomic behavior between resting and evoked states, resulting in a functional brain-wide reorganization with local underpinnings, which reconciles evidence from the human literature. The 3xTgAD tauopathy profile resembles that in AD patients closely, suggesting that similar pathophysiological mechanisms might underlie network dysfunction in clinical cases.