Effects of chronic exposure to haloperidol, olanzapine or lithium on SV2A and NLGN synaptic puncta in the rat frontal cortex

Halff, Els F.; Côtel, Marie-Caroline; Natesan, Sridhar; McQuade, R; Ottley, Chris J.; Srivastava, Deepak P.; Howes, Oliver; Vernon, Anthony C.

doi:10.1016/j.bbr.2021.113203

Cited by 12 publications

(17 citation statements)

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“…The administration of antipsychotic drugs failed to change SV2A levels in frontal cortex of healthy rats determined by [ 3 H]UCB-J autoradiography and immunohistochemistry, implying that antipsychotic medications have no effect on SV2A expression ( Onwordi et al, 2020 ). A later study reported that neither the chronic exposure to antipsychotic drugs such as haloperidol and olanzapine, nor the administration of lithium had effects on SV2A levels, measured with immunochemistry ( Halff et al, 2021 ).…”

Section: Synaptic Vesicle Glycoprotein 2a and Positron Emission Tomog...mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A: Features and Functions

et al. 2022

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In recent years, the field of neuroimaging dramatically moved forward by means of the expeditious development of specific radioligands of novel targets. Among these targets, the synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles, present in all synaptic terminals, irrespective of neurotransmitter content. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. The ubiquitous expression in gray matter regions of the brain is the basis of its candidacy as a marker of synaptic density. Following the development of molecules derived from the structure of the anti-epileptic drug levetiracetam, which selectively binds to SV2A, several radiolabeled markers have been synthetized to allow the study of SV2A distribution with positron emission tomography (PET). These radioligands permit the evaluation of in vivo changes of SV2A distribution held to be a potential measure of synaptic density in physiological and pathological conditions. The use of SV2A as a biomarker of synaptic density raises important questions. Despite numerous studies over the last decades, the biological function and the expressional properties of SV2A remain poorly understood. Some functions of SV2A were claimed, but have not been fully elucidated. While the expression of SV2A is ubiquitous, stronger associations between SV2A and Υ amino butyric acid (GABA)-ergic rather than glutamatergic synapses were observed in some brain structures. A further issue is the unclear interaction between SV2A and its tracers, which reflects a need to clarify what really is detected with neuroimaging tools. Here, we summarize the current knowledge of the SV2A protein and we discuss uncertain aspects of SV2A biology and physiology. As SV2A expression is ubiquitous, but likely more strongly related to a certain type of neurotransmission in particular circumstances, a more extensive knowledge of the protein would greatly facilitate the analysis and interpretation of neuroimaging results by allowing the evaluation not only of an increase or decrease of the protein level, but also of the type of neurotransmission involved.

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Section: Synaptic Vesicle Glycoprotein 2a and Positron Emission Tomog...mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A: Features and Functions

et al. 2022

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“…All but one of the schizophrenia subjects were taking antipsychotic medication. Recent studies found no effect of haloperidol or olanzapine administration on SV2A protein levels or specific binding in the rat brain, suggesting antipsychotic treatment is unlikely to affect the [ 11 C]UCB-J measure in schizophrenia patients [30,62]. There is some, albeit inconsistent evidence that antipsychotic drug administration may reduce glutamate levels in schizophrenia, with four of eight of published studies showing significant reductions (in the frontal and left temporal cortices, left thalamus and right striatum) following antipsychotic drug administration in schizophrenia while the other half show no significant change [63].…”

Section: Strengths and Limitationsmentioning

confidence: 99%

The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study

et al. 2021

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Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.

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“…The use of autoradiography for quantification of synaptic density in preclinical research has been made possible by the development of SV2A radiotracers, described in more detail in the following section. These radiotracers have been used to map the expression of the presynaptic SV2A protein in the brain of WT and transgenic animals (Menten-Dedoyart et al, 2016;Varnäs et al, 2020), to evaluate changes in synaptic density in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease and the quinolinic acid model of Huntington's disease (Thomsen et al, 2021), and to study the effect of different drugs and treatments (Onwordi et al, 2020;Binda et al, 2021;Halff et al, 2021;Raval et al, 2021b).…”

Section: Other Post-mortem Methods: Autoradiographymentioning

confidence: 99%

Imaging Synaptic Density: The Next Holy Grail of Neuroscience?

et al. 2022

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The brain is the central and most complex organ in the nervous system, comprising billions of neurons that constantly communicate through trillions of connections called synapses. Despite being formed mainly during prenatal and early postnatal development, synapses are continually refined and eliminated throughout life via complicated and hitherto incompletely understood mechanisms. Failure to correctly regulate the numbers and distribution of synapses has been associated with many neurological and psychiatric disorders, including autism, epilepsy, Alzheimer’s disease, and schizophrenia. Therefore, measurements of brain synaptic density, as well as early detection of synaptic dysfunction, are essential for understanding normal and abnormal brain development. To date, multiple synaptic density markers have been proposed and investigated in experimental models of brain disorders. The majority of the gold standard methodologies (e.g., electron microscopy or immunohistochemistry) visualize synapses or measure changes in pre- and postsynaptic proteins ex vivo. However, the invasive nature of these classic methodologies precludes their use in living organisms. The recent development of positron emission tomography (PET) tracers [such as (18F)UCB-H or (11C)UCB-J] that bind to a putative synaptic density marker, the synaptic vesicle 2A (SV2A) protein, is heralding a likely paradigm shift in detecting synaptic alterations in patients. Despite their limited specificity, novel, non-invasive magnetic resonance (MR)-based methods also show promise in inferring synaptic information by linking to glutamate neurotransmission. Although promising, all these methods entail various advantages and limitations that must be addressed before becoming part of routine clinical practice. In this review, we summarize and discuss current ex vivo and in vivo methods of quantifying synaptic density, including an evaluation of their reliability and experimental utility. We conclude with a critical assessment of challenges that need to be overcome before successfully employing synaptic density biomarkers as diagnostic and/or prognostic tools in the study of neurological and neuropsychiatric disorders.

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Effects of chronic exposure to haloperidol, olanzapine or lithium on SV2A and NLGN synaptic puncta in the rat frontal cortex

Cited by 12 publications

References 64 publications

Synaptic Vesicle Glycoprotein 2A: Features and Functions

Synaptic Vesicle Glycoprotein 2A: Features and Functions

The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study

Imaging Synaptic Density: The Next Holy Grail of Neuroscience?

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