3d Synaptic Organization of the Rat Ca1 and Alterations Induced by Cocaine Self-Administration

Abstract

The hippocampus plays a key role in contextual conditioning and has been proposed as an important component of the cocaine addiction brain circuit.To gain knowledge about cocaine-induced alterations in this circuit, we used Focused Ion Beam milling/Scanning Electron Microscopy (FIB/SEM) to reveal and quantify the 3D synaptic organization of the stratum radiatum of rat CA1, under normal circumstances and after cocaine-self administration (SA). Most synapses are asymmetric (excitatory), macular-shaped, and in contact with spine heads. After cocaine-SA, the size and complexity of both asymmetric and symmetric (inhibitory) synapses increased but no changes were observed in the synaptic density.This work constitutes the first detailed report on the 3D synaptic organization in the stratum radiatum of the CA1 field of cocaine-SA rats. Our data contribute to the elucidation of the normal and altered synaptic organization of the hippocampus, which is crucial for better understanding the neurobiological mechanisms underlying cocaine addiction.

Three-dimensional synaptic organization of the human hippocampal CA1 field

“…In the present study, the density of inhibitory synapses was particularly low in most CA1 layers (AS:SS ratio in all layers was around 95:5 except for in SLM, where the ratio was close to 90:10). This data is in line with our study using FIB/SEM to analyze the synaptic density in the mouse (where the proportion of synapses that were inhibitory was 8% in the SLM, and approximately 2% in the case of the SR and SO) ( Santuy et al, 2020 ) and in the rat CA1 field (where 4% of the synapses in SR were inhibitory) ( Blazquez-Llorca et al, 2020 ).…”

“…Considering all synapses, excitatory contacts were larger than inhibitory ones, as has also been observed in layer II of the human transentorhinal cortex ( Domínguez-Álvaro et al, 2018 ); however, this contrasted with the findings in the somatosensory cortex ( Santuy et al, 2018b ) and SR of CA1 in the rat ( Blazquez-Llorca et al, 2020 ). A tendency towards axodendritic synapses being bigger than axospinous synapses was also observed; however, this difference was only significant in the case of SLM synapses.…”

“…These values are much higher than the ones found in the present work for the human CA1 ( Table 1 ). Such huge differences in synaptic density between humans and rodents —together with the above-mentioned divergences in the morphology and distribution of pyramidal cells in the SP of CA1 ( Benavides-Piccione et al, 2020 ), as well as differences in other anatomical, genetic, molecular and physiological features ( Benavides-Piccione et al, 2020 ; Blazquez-Llorca et al, 2020 ; Ding, 2013 ; Hawrylycz et al, 2012 ; Santuy et al, 2020 ; Tapia-González et al, 2020 ; van Dijk et al, 2016 )— further support the notion that there are remarkable differences between the human and rodent CA1. These differences clearly need to be taken into consideration when making interpretations in translational studies comparing one species to another.…”

“…Since no quantitative 3D analysis of the synaptic organization in the human hippocampus has been performed before, our data could not be compared to previous reports. However, in recent studies from our group using FIB/SEM to analyze the synaptic density in the rodent CA1 field, the following values were obtained: 2.53 synapses/µm 3 in SO, 2.36 synapses/µm 3 in SR and 1.72 synapses/µm 3 in SLM in the mouse ( Santuy et al, 2020 ), and 2.52 synapses/µm 3 in SR in the rat ( Blazquez-Llorca et al, 2020 ). These values are much higher than the ones found in the present work for the human CA1 ( Table 1 ).…”