Synaptic architecture shapes regional dynamics in the mouse brain
Poster No:
1198
Submission Type:
Abstract Submission
Authors:
Justine Hansen1, Andrea Luppi2, Zhen Qiu3, Silvia Gini4, Ben Fulcher5, Alessandro Gozzi6, Seth Grant7, Bratislav Misic8
Institutions:
1McGill University, Montreal, QC, 2University of Oxford, Cambridge, Cambridgeshire, 3University of Dundee, Dundee, NA, 4Istituto Italiano di Tecnologia, Rovereto, Trentino, 5University of Sydney, Sydney, Australia, 6Istituto Italiano di Tecnologia, Rovereto, Trento, 7University of Edinburgh, Edinburgh, NA, 8Montreal Neurological Institute, Montreal, Quebec
First Author:
Co-Author(s):
Introduction:
Synapses are the connections that transform neurons from simple electrically charged cells into complex circuits that support perception, cognition and action. Recent advances in single-punctum synapse mapping in mice have made it possible to study the diversity of synapses and how synapse types are differentially expressed throughout the brain [1]. Two synaptic proteins in particular are well-suited candidates for genetic tagging in mouse models: postsynaptic density 95 (PSD95) and synapse-associated protein 102 (SAP102). These two postsynaptic scaffolding proteins are stably and abundantly expressed in excitatory synapses, assemble receptors, channels, and other signaling molecules into multiprotein signaling complexes, and play a direct role in shaping the synapse's response to a neural signal [2,3]. Importantly, synapses that express only PSD95 versus those that express only SAP102 are differentially expressed in the brain, such that each brain region has its own unique synaptic composition. This regional heterogeneity of synaptic architecture suggests that different brain regions are equipped to generate different patterns of neural dynamics.
Methods:
Here we ask whether the dynamical phenotype of a brain region can be traced back to its underlying synaptic phenotypes. PSD95 and SAP102 synapse density was mapped throughout the whole mouse brain using fluorescent labelling and spinning disk confocal microscopy [1]. Next, fMRI recordings were acquired in 10 awake mice [4]. To comprehensively phenotype the dynamic signature of each brain region, we use the highly comparative time-series analysis (hctsa) toolbox to compute 6,471 features of each fMRI time-series in every region and mouse, including measurements of autocorrelation, entropy, frequency composition, signal amplitude distribution, and predictability [5,6] (Figure 1c). We calculate the absolute Spearman correlation between each time-series feature and synapse density, for PSD95 and SAP102 synapses separately (Figure 1d). After establishing that each synapse type is associated with specific dynamics, we test whether a region's synaptic profile influences its embedding in global structural and functional networks (Figure 2). We use tract-tracing data from the Allen Mouse Brain Connectivity Atlas [7] (Figure 2a) as well as functional connectivity from the same time-series as above (Figure 2e), and compare the location of hubs with the density of different synapse types. Finally, using two fMRI datasets acquired on anaesthetized mice [4], we test whether the functional role of a synapse type is ubiquitous across awake and anaesthetized behavioural states, or whether some synapses play a larger role during wakefulness.
Results:
We find that PSD95 synapses are associated with time-series features that reflect the predictability and variability of the time-series (Figure 1d,e). Furthermore, these synapses are more likely to be present in functionally specialized regions and are anticorrelated with functional hubs (Figure 2f). Meanwhile, regions that are enriched for SAP synapses display functional activity with frequent high-amplitude events and are more likely to establish long-term afferent and efferent connections (Figure 1d,f, Figure 2b,c). Finally, we find that some synapse types (e.g. short-lifetime PSD95) may be specifically used when awake, while others (e.g. long-lifetime PSD95, SAP102) may play a fundamental role in brain functioning that does not depend on behavioural state.
Conclusions:
In summary, we present synapse type distribution as a novel molecular feature with direct influence on regional dynamics. As a result, the synaptic composition of a brain region affects its participation in whole-brain structural and functional networks, as well as in different behavioural states. Altogether, this work illustrates the fundamental role of synapses in shaping whole-brain organization.
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural) 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Neuroanatomy Other 2
Keywords:
ANIMAL STUDIES
Consciousness
FUNCTIONAL MRI
1|2Indicates the priority used for review
Abstract Information
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