Abstract
Synaptosomes are isolated nerve terminals that contain synaptic components, including neurotransmitters, metabolites, adhesion/fusion proteins, and nerve terminal receptors. The essential role of synaptosomes in neurotransmission has stimulated keen interest in understanding both their proteomic and metabolic composition. Mass spectrometric (MS) quantification of synaptosomes has illuminated their proteomic composition, but the determination of the metabolic composition by MS has been met with limited success. In this study, we report a proof-of-concept application of one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy for analyzing the metabolic composition of synaptosomes. We utilize this approach to compare the metabolic composition synaptosomes from a wild-type rat with that from a newly generated genetic rat model (Disc1 svΔ2), which qualitatively recapitulates clinically observed early DISC1 truncations associated with schizophrenia. This study demonstrates the feasibility of using NMR spectroscopy to identify and quantify metabolites within synaptosomal fractions.
Highlights
Synaptosomes are isolated nerve terminals that contain synaptic components such as neurotransmitters, metabolites, and nerve terminal receptors, and they represent an important component in neurotransmission and synaptic plasticity [1,2,3]
The outsized contribution of DISC1 in the neuropathogenesis of schizophrenia is largely attributable to its role in early neurodevelopment
As with other genetic variants that have been shown to confer an increased risk for disease [20], the balanced chromosomal t(1;11)(q42.1; q14.3) translocation of the DISC1 gene has been implicated in several psychiatric illnesses, including schizophrenia and developmental disorders [37,38,39], bipolar disorder [39], autism spectrum disorder (ASD) [40], and major depressive disorder [41]
Summary
Synaptosomes are isolated nerve terminals that contain synaptic components such as neurotransmitters, metabolites, and nerve terminal receptors, and they represent an important component in neurotransmission and synaptic plasticity [1,2,3]. Metabolites 2020, 10, 79 unanticipated genetic [6,7,8], molecular [9], and neurostructural [10,11] similarities of several psychiatric diseases, including autism spectrum disorder (ASD), schizophrenia, bipolar disorder, and major depression, there is renewed interest in understanding the functional biological changes underlying psychiatric illness, especially at the level of the synapse Reports underscoring this renewed interest are those dissecting the role of serotonin in major depressive disorder and anxiety disorders [12,13,14,15,16,17], along with studies examining perturbations in glutamate homeostasis that may contribute to diverse neurologic and psychiatric illnesses such as major depressive disorder and anxiety disorders, as well as Alzheimer’s disease [18,19]. The outsized contribution of DISC1 in the neuropathogenesis of schizophrenia is largely attributable to its role in early neurodevelopment
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