Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats

Onwordi, Ellis Chika; Halff, Els F.; Whitehurst, Thomas; Mansur, Ayla; Côtel, Marie-Caroline; Wells, Lisa; Creeney, Hannah; Bonsall, David R.; Rogdaki, Maria; Shatalina, Ekaterina; Marques, Tiago Reis; Rabiner, Eugenii A.; Gunn, Roger N.; Natesan, Sridhar; Vernon, Anthony C.; Howes, Oliver

doi:10.1038/s41467-019-14122-0

Cited by 168 publications

(174 citation statements)

References 85 publications

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“…SV2A is thought to play a role in neurotransmitter release and vesicle recycling [15][16][17][18] , and, due its localisation at both inhibitory and excitatory synapses throughout the brain, is considered as a proxy for overall synaptic density. Consistent with the aforementioned post-mortem evidence, studies using [ 11 C]-UCB-J PET imaging provide evidence for a reduction in SV2A binding in chronic SCZ 19 . Whilst there is also evidence for reduced SV2A ligand binding in major depressive disorder 16 , data for BD is as yet lacking.…”

Section: Introductionsupporting

confidence: 68%

“…To gain further insight into the effect of psychotropic medication on synaptic density, we therefore investigated the effects of HAL, OLZ, and Li treatments on SV2A and Neuroligin (NLGN) clusters as global pre-and postsynaptic marker, respectively. We hypothesised that cluster count would be unaffected by chronic exposure to either HAL or OLZ, concurrent with our earlier data 19 , however we anticipated that chronic exposure to Li, which has been suggested to have neurotrophic and neuroprotective effects 21,27 , would lead to an increase in synaptic clusters. Our research provides one of the first investigations into the effect of these different psychotropic medications on SV2A clusters.…”

Section: Introductionmentioning

confidence: 53%

“…Samples sizes were based on prior studies 19,25,26 . Two animals (one VEH-treated and one OLZ-treated) were excluded from cluster analysis on the basis of sub-optimal saline perfusion of the brain, which negatively impacted on staining quality.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent study in chronic SCZ patients also demonstrated that total SV2A protein levels and [ 3 H]-UCB-J radioligand specific binding in the rat frontal cortex were unaffected by chronic exposure to two different antipsychotic drugs (APD) 19 . These data suggest that the reduced SV2A ligand binding observed in patients is related to SCZ pathophysiology rather than an effect of antipsychotic treatment.…”

Section: Introductionmentioning

confidence: 91%

“…Blood plasma levels achieved using these doses and delivery by osmotic pumps are consistent with clinically comparable dopamine D2 receptor (D2R) occupancy and plasma levels 25,26,29 . With the exception of Li-treated animals, data reported in this study is derived from the same animals as those used in our previous study 19 .…”

Section: Experimental Design (Animals)mentioning

confidence: 99%

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Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

Halff

Cotel

Natesan

et al. 2020

Preprint

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The pathophysiology of the majority of neuropsychiatric disorders, including schizophrenia and mood disorders, involves synaptic dysfunction and/or loss, manifesting as lower levels of several presynaptic and postsynaptic marker proteins. Whether chronic exposure to antipsychotic drugs may contribute to this pattern of synaptic loss remains controversial. In contrast, the mood stabiliser lithium has shown to exhibit neurotrophic actions and is thought to enhance synapse formation. Whilst these data are not unequivocal, they suggest that antipsychotic drugs and lithium have contrasting effects on synapse density. We therefore investigated the effect of chronic exposure to lithium and to two different antipsychotics, haloperidol and olanzapine, on presynaptic Synaptic Vesicle glycoprotein 2A (SV2A) and postsynaptic Neuroligin (NLGN) clusters in the rat frontal cortex. Chronic exposure (28 days) to haloperidol (0.5 mg/kg/d) or olanzapine (7.5 mg/kg/d) had no effect on either SV2A or NLGN clusters and no overall effect on synaptic clusters. In contrast, chronic lithium exposure (2 mmol/L eq./d) significantly increased NLGN cluster density as compared to vehicle, but did not affect either SV2A or total synaptic clusters. These data are consistent with and extend our prior work, confirming no effect of either antipsychotics or lithium on SV2A clustering, but suggest contrasting effects of these drugs on the post-synapse. Although caution needs to be exerted when extrapolating results from animals to patients, these data provide clarity with regard to the effect of antipsychotics and lithium on synaptic markers, thus facilitating discrimination of drug from illness effects in human studies of synaptic pathology in psychiatric disorders.

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Section: Introductionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Experimental Design (Animals)mentioning

confidence: 99%

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Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

Halff

Cotel

Natesan

et al. 2020

Preprint

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Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis

Chopra,

Segal,

Oldham

et al. 2023

JAMA Psychiatry

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ImportancePsychotic illness is associated with anatomically distributed gray matter reductions that can worsen with illness progression, but the mechanisms underlying the specific spatial patterning of these changes is unknown.ObjectiveTo test the hypothesis that brain network architecture constrains cross-sectional and longitudinal gray matter alterations across different stages of psychotic illness and to identify whether certain brain regions act as putative epicenters from which volume loss spreads.Design, Settings, and ParticipantsThis case-control study included 534 individuals from 4 cohorts, spanning early and late stages of psychotic illness. Early-stage cohorts included patients with antipsychotic-naive first-episode psychosis (n = 59) and a group of patients receiving medications within 3 years of psychosis onset (n = 121). Late-stage cohorts comprised 2 independent samples of people with established schizophrenia (n = 136). Each patient group had a corresponding matched control group (n = 218). A sample of healthy adults (n = 356) was used to derive representative structural and functional brain networks for modeling of network-based spreading processes. In Longitudinal illness-related and antipsychotic-related gray matter changes over 3 and 12 months were examined using a triple-blind randomized placebo-control magnetic resonance imaging study of the antipsychotic-naive patients. All data were collected between April 29, 2008, and January 15, 2020, and analyses were performed between March 1, 2021, and January 14, 2023.Main Outcomes and MeasuresCoordinated deformation models were used to estimate the extent of gray matter volume (GMV) change in each of 332 parcellated areas by the volume changes observed in areas to which they were structurally or functionally coupled. To identify putative epicenters of volume loss, a network diffusion model was used to simulate the spread of pathology from different seed regions. Correlations between estimated and empirical spatial patterns of GMV alterations were used to quantify model performance.ResultsOf 534 included individuals, 354 (66.3%) were men, and the mean (SD) age was 28.4 (7.4) years. In both early and late stages of illness, spatial patterns of cross-sectional volume differences between patients and controls were more accurately estimated by coordinated deformation models constrained by structural, rather than functional, network architecture (r range, &gt;0.46 to &lt;0.57; P &lt; .01). The same model also robustly estimated longitudinal volume changes related to illness (r ≥ 0.52; P &lt; .001) and antipsychotic exposure (r ≥ 0.50; P &lt; .004). Network diffusion modeling consistently identified, across all 4 data sets, the anterior hippocampus as a putative epicenter of pathological spread in psychosis. Epicenters of longitudinal GMV loss were apparent in posterior cortex early in the illness and shifted to the prefrontal cortex with illness progression.Conclusion and RelevanceThese findings highlight a central role for white matter fibers as conduits for the spread of pathology across different stages of psychotic illness, mirroring findings reported in neurodegenerative conditions. The structural connectome thus represents a fundamental constraint on brain changes in psychosis, regardless of whether these changes are caused by illness or medication. Moreover, the anterior hippocampus represents a putative epicenter of early brain pathology from which dysfunction may spread to affect connected areas.

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PET imaging of synaptic density in Parkinsonian disorders

Martin,

Uribe,

Strafella

2023

J of Neuroscience Research

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Synaptic dysfunction and altered synaptic pruning are present in people with Parkinsonian disorders. Dopamine loss and alpha‐synuclein accumulation, two hallmarks of Parkinson's disease (PD) pathology, contribute to synaptic dysfunction and reduced synaptic density in PD. Atypical Parkinsonian disorders are likely to have unique spatiotemporal patterns of synaptic density, differentiating them from PD. Therefore, quantification of synaptic density has the potential to support diagnoses, monitor disease progression, and treatment efficacy. Novel radiotracers for positron emission tomography which target the presynaptic vesicle protein SV2A have been developed to quantify presynaptic density. The radiotracers have successfully investigated synaptic density in preclinical models of PD and people with Parkinsonian disorders. Therefore, this review will summarize the preclinical and clinical utilization of SV2A radiotracers in people with Parkinsonian disorders. We will evaluate how SV2A abundance is associated with other imaging modalities and the considerations for interpreting SV2A in Parkinsonian pathology.

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Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats

Cited by 168 publications

References 85 publications

Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis

PET imaging of synaptic density in Parkinsonian disorders

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