Differential Expression of Synapsin I and II upon Treatment by Lithium and Valproic Acid in Various Brain Regions

Joshi, Hetshree; Sharma, Roohie; Prashar, Shreya; Ho, Joella; Thomson, Sharon; Mishra, Ram K.

doi:10.1093/ijnp/pyy023

Cited by 7 publications

(6 citation statements)

References 46 publications

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“…reached plasma lithium levels of: 1.07±0.039 mmol/L after treatment, concentrations similar to those reached in patients under lithium therapy [30,52]. Lithium-treated Ank3 p.W1989R mice showed higher spontaneous inhibitory postsynaptic current (sIPSC) frequency compared to vehicletreated Ank3 p.W1989R mice (Fig.…”

Section: Introductionsupporting

confidence: 69%

“…To explore if lithium treatment modifies inhibitory neurotransmission in Ank3 p.W1989R mice, we performed whole-cell patch-clamp recordings in pyramidal neurons in WT, Ank3 p.W1989R, and Ank3 p.W1989R mice treated with lithium for 19-21 days. Ank3 p.W1989R littermates given lithium reached plasma lithium levels of: 1.07±0.039 mmol/L after treatment, concentrations similar to those reached in patients under lithium therapy [30,52]. Lithium-treated Ank3 p.W1989R mice showed higher spontaneous inhibitory postsynaptic current (sIPSC) frequency compared to vehicle-treated Ank3 p.W1989R mice (Fig.…”

Section: Resultsmentioning

confidence: 60%

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Effects of chronic lithium treatment on neuronal excitability and GABAergic transmission in anAnk3mutant mouse model

Caballero-Florán,

Nelson,

Min

et al. 2023

Preprint

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Bipolar disorder (BD) is a common psychiatric disease that can lead to psychosocial disability, decreased quality of life, and high risk for suicide. Genome-wide association studies have shown that theANK3gene is a significant risk factor for BD, but the mechanisms involved in BD pathophysiology are not yet fully understood. Previous work has shown that ankyrin-G, the protein encoded byANK3, stabilizes inhibitory synapses in vivo through its interaction with the GABAAreceptor-associated protein (GABARAP). We generated a mouse model with a missense p.W1989R mutation inAnk3, that abolishes the interaction between ankyrin-G and GABARAP, which leads to reduced inhibitory signaling in the somatosensory cortex and increased pyramidal cell excitability. Humans with the same mutation exhibit BD symptoms, which can be attenuated with lithium therapy. In this study, we describe that chronic treatment ofAnk3p.W1989R mice with lithium normalizes neuronal excitability in cortical pyramidal neurons and increases inhibitory GABAergic postsynaptic currents. The same outcome in inhibitory transmission was observed when mice were treated with the GSK-3β inhibitor Tideglusib. These results suggest that lithium treatment modulates the excitability of pyramidal neurons in the cerebral cortex by increasing GABAergic neurotransmission, likely via GSK-3 inhibition. In addition to the importance of these findings regardingANK3variants as a risk factor for BD development, this study may have significant implications for treating other psychiatric disorders associated with alterations in inhibitory signaling, such as schizophrenia, autism spectrum disorder, and major depressive disorder.

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Section: Introductionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 60%

Effects of chronic lithium treatment on neuronal excitability and GABAergic transmission in anAnk3mutant mouse model

Caballero-Florán,

Nelson,

Min

et al. 2023

Preprint

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“…Studies on the effects of chronic Li exposure on SYN reported no effect on either protein 40,41 or mRNA levels 49 . On the other hand, Li exposure was shown to increase mRNA levels of Synapsins, a class of proteins that like SV2A and SYN is located on presynaptic vesicles and is involved in neurotransmitter release 22 , and is reduced in BD 40 . The latter study, however, did not see an effect of Li on Synapsin protein levels in the hippocampus.…”

Section: Summary and Interpretation Of Resultsmentioning

confidence: 99%

“…In this context, several studies investigating the effect of antipsychotic and mood-stabilising medication on the animal brain provide evidence to suggest that synaptic changes may occur upon administration of these drugs. These include altered spine density 20 , dendritic branching 21 , and altered expression of synaptic protein markers such as Synapsin, SNAP-25, Synaptophysin, and PSD-95 [22][23][24] , however SV2A was not assessed in these studies. In earlier work we demonstrated contrasting effects of the antipsychotic drugs Haloperidol (HAL) and…”

Section: Introductionmentioning

confidence: 99%

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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“…Although the genes encoding the presynaptic proteins have been studied in relation to different neurodevelopmental/psychiatric disorders, including ASD, the expression of the key proteins responsible for synapse formation, maintenance of their proper structure, and neurotransmitter release was not investigated. So far, the single nucleotide polymorphisms and mutations in the genes coding synaptic proteins have been examined [3,13,[20][21][22][23][43][44][45][46]. This suggests that the synapse is a possible site of autism origin.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Exposure to Valproic Acid Affects Microglia and Synaptic Ultrastructure in a Brain-Region-Specific Manner in Young-Adult Male Rats: Relevance to Autism Spectrum Disorders

Gąssowska-Dobrowolska

Cieślik

Czapski

et al. 2020

IJMS

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Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions categorized as synaptopathies. Environmental risk factors contribute to ASD aetiology. In particular, prenatal exposure to the anti-epileptic drug valproic acid (VPA) may increase the risk of autism. In the present study, we investigated the effect of prenatal exposure to VPA on the synaptic morphology and expression of key synaptic proteins in the hippocampus and cerebral cortex of young-adult male offspring. To characterize the VPA-induced autism model, behavioural outcomes, microglia-related neuroinflammation, and oxidative stress were analysed. Our data showed that prenatal exposure to VPA impaired communication in neonatal rats, reduced their exploratory activity, and led to anxiety-like and repetitive behaviours in the young-adult animals. VPA-induced pathological alterations in the ultrastructures of synapses accompanied by deregulation of key pre- and postsynaptic structural and functional proteins. Moreover, VPA exposure altered the redox status and expression of proinflammatory genes in a brain region-specific manner. The disruption of synaptic structure and plasticity may be the primary insult responsible for autism-related behaviour in the offspring. The vulnerability of specific synaptic proteins to the epigenetic effects of VPA may highlight the potential mechanisms by which prenatal VPA exposure generates behavioural changes.

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Differential Expression of Synapsin I and II upon Treatment by Lithium and Valproic Acid in Various Brain Regions

Cited by 7 publications

References 46 publications

Effects of chronic lithium treatment on neuronal excitability and GABAergic transmission in anAnk3mutant mouse model

Effects of chronic lithium treatment on neuronal excitability and GABAergic transmission in anAnk3mutant mouse model

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

Prenatal Exposure to Valproic Acid Affects Microglia and Synaptic Ultrastructure in a Brain-Region-Specific Manner in Young-Adult Male Rats: Relevance to Autism Spectrum Disorders

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