Three‐dimensional relationships between perisynaptic astroglia and human hippocampal synapses

Abstract

Perisynaptic astroglia are critical for normal synaptic development and function. Little is known, however, about perisynaptic astroglia in the human hippocampus. When mesial temporal lobe epilepsy (MTLE) is refractory to medication, surgical removal is required for seizure quiescence. To investigate perisynaptic astroglia in human hippocampus, we recovered slices for several hours in vitro from three surgical specimens and then quickly fixed them to achieve high-quality ultrastructure. Histological samples from each case were found to have mesial temporal sclerosis with Blumcke Type 1a (mild, moderate) or 1b (severe) pathology. Quantitative analysis through serial section transmission electron microscopy in CA1 stratum radiatum revealed more synapses in the mild (10/10 µm 3 ) than the moderate (5/10 µm 3 ) or severe (1/10 µm 3 ) cases. Normal spines occurred in mild and moderate cases, but a few multisynaptic spines were all that remained in the severe case. Like adult rat hippocampus, perisynaptic astroglial processes were preferentially associated with larger synapses in the mild and moderate cases, but rarely penetrated the cluster of axonal boutons surrounding multisynaptic spines. Synapse perimeters were only partially surrounded by astroglial processes such that all synapses had some access to substances in the extracellular space, similar to adult rat hippocampus. Junctions between astroglial processes were observed more frequently in moderate than mild case, but were obscured by densely packed intermediate filaments in astroglial processes of the severe case. These findings suggest that perisynaptic astroglial processes associate with synapses in human hippocampus in a manner similar to model systems and are disrupted by severe MTLE pathology.

Do glia drive synaptic and cognitive impairment in disease?

“…It is estimated that one cortical astrocyte in the mouse brain can ensheath multiple neuronal cell somas, 300-600 dendrites, and more than 100,000 synapses. More than 90% of spines in the mouse barrel cortex are in contact with astrocytic processes 5 , and similar synaptic ensheathment by astrocytes is also present in the human brain 6 . This close physical association between synapses and astrocytic processes enables astrocytes to function as the first cellular responders to various changes in synaptic activity during development and adulthood.…”

Strategies for immunohistochemical protein localization using antibodies: What did we learn from neurotransmitter transporters in glial cells and neurons

“…A plasma membrane is about 5 nm thick and the width of the extracellular space (the distances between neighboring cellular extensions) is typically in the range 20-40 nm, while the diameter of a glutamate transporter trimer is believed to be about 8 nm (Yernool et al, 2004). Cellular elements are tightly intermingled (Kirov et al, 1999;Sorra and Harris, 2000;Witcher et al, 2010;Harris and Weinberg, 2012;Mathiisen et al, 2010). This is schematically illustrated in figure 8.…”

Nanoscale analysis of structural synaptic plasticity

“…The absence of astroglial processes gives the impression of more extracellular space in submersion-based slice preparations. In fact, their loss is of great concern for understanding mechanisms of structural synaptic plasticity because perisynaptic astroglial processes are linked to synaptogenesis and subsequent stabilization both during development [25;26], and in mature brain slices [11;27]. …”