Publications by authors named "Anisa Dehghani"

6 Publications

  • Page 1 of 1

Widespread brain parenchymal HMGB1 and NF-κB neuroinflammatory responses upon cortical spreading depolarization in familial hemiplegic migraine type 1 mice.

Neurobiol Dis 2021 Aug 10;156:105424. Epub 2021 Jun 10.

Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey. Electronic address:

Neuroinflammatory changes involving neuronal HMGB1 release and astrocytic NF-κB nuclear translocation occur following cortical spreading depolarization (CSD) in wildtype (WT) mice but it is unknown to what extent this occurs in the migraine brain. We therefore investigated in familial hemiplegic migraine type 1 (FHM1) knock-in mice, which express an intrinsic hyperexcitability phenotype, the extent of neuroinflammation without and after CSD. CSD was evoked in one hemisphere by pinprick (single CSD) or topical KCl application (multiple CSDs). Neuroinflammatory (HMGB1, NF-κB) and neuronal activation (pERK) markers were investigated by immunohistochemistry in the brains of WT and FHM1 mutant mice without and after CSD. Effects of NMDA receptor antagonism on basal and CSD-induced neuroinflammatory changes were examined by, respectively, systemically administered MK801 and ifenprodil or topical MK801 application. In FHM1 mutant mice, CSD caused enhanced neuronal HMGB1 release and astrocytic NF-κB nuclear translocation in the cortex and subcortical areas that were equally high in both hemispheres. In WT mice such effects were only pronounced in the hemisphere in which CSD was induced. Neuroinflammatory responses were associated with pERK expression indicating neuronal activation. Upon CSD, contralateral cortical and striatal HMGB1 release was reduced by topical application of MK801 in the hemisphere contralateral to the one in which CSD was induced. This study reveals that neuroinflammatory activation after CSD is widespread and extends to the contralateral hemisphere, particularly in brains of FHM1 mutant mice. Effective blockade of CSD-induced neuroinflammatory responses in the contralateral hemisphere in FHM1 mice by local NMDA receptor antagonism suggests that neuronal hyperexcitability-related neuroinflammation is relevant in migraine pathophysiology, but possibly also other neurological disorders in which spreading depolarization is involved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2021.105424DOI Listing
August 2021

Impaired θ-γ Coupling Indicates Inhibitory Dysfunction and Seizure Risk in a Dravet Syndrome Mouse Model.

J Neurosci 2021 01 24;41(3):524-537. Epub 2020 Nov 24.

Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied θ-γ coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical θ-γ coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. θ-γ Coupling was partly restored by cannabidiol (CBD). Locally disrupting Na1.1 expression in the hippocampus or cortex yielded early attenuation of θ-γ coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells (BCs). Our results indicate attenuated θ-γ coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2132-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821857PMC
January 2021

Focal and generalized seizure activity after local hippocampal or cortical ablation of Na 1.1 channels in mice.

Epilepsia 2020 04 19;61(4):e30-e36. Epub 2020 Mar 19.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Early onset seizures are a hallmark of Dravet syndrome. Previous studies in rodent models have shown that the epileptic phenotype is caused by loss-of-function of voltage-gated Na 1.1 sodium channels, which are chiefly expressed in γ-aminobutyric acid (GABA)ergic neurons. Recently, a possibly critical role has been attributed to the hippocampus in the seizure phenotype, as local hippocampal ablation of Na 1.1 channels decreased the threshold for hyperthermia-induced seizures. However, the effect of ablation of Na 1.1 channels restricted to cortical sites has not been tested. Here we studied local field potential (LFP) and behavior in mice following local hippocampal and cortical ablation of Scn1a, a gene encoding the α1 subunit of Na 1.1 channels, and we compared seizure characteristics with those of heterozygous global knockout Scn1 mice. We found a high incidence of spontaneous seizures following either local hippocampal or cortical ablation, notably during a transient time window, similar to Scn1a mice. Nonconvulsive seizure activity in the injected area was common and preceded generalized seizures. Moreover, mice were susceptible to hyperthermia-induced seizures. In conclusion, local ablation of Na 1.1 channels in the hippocampus and cortex results in focal seizure activity that can generalize. These data indicate that spontaneous epileptic activity may initiate in multiple brain regions in Dravet syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216883PMC
April 2020

First FHM3 mouse model shows spontaneous cortical spreading depolarizations.

Ann Clin Transl Neurol 2020 01 27;7(1):132-138. Epub 2019 Dec 27.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Here we show, for the first time, spontaneous cortical spreading depolarization (CSD) events - the electrophysiological correlate of the migraine aura - in animals by using the first generated familial hemiplegic migraine type 3 (FHM3) transgenic mouse model. The mutant mice express L263V-mutated α1 subunits in voltage-gated Na 1.1 sodium channels (Scn1a ). CSDs consistently propagated from visual to motor cortex, recapitulating what has been shown in patients with migraine with aura. This model may be valuable for the preclinical study of migraine with aura and other diseases in which spreading depolarization is a prominent feature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.50971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952313PMC
January 2020

Mouse Models of Familial Hemiplegic Migraine for Studying Migraine Pathophysiology.

Curr Neuropharmacol 2019 ;17(10):961-973

Institute of Neurological Sciences and Psychiatry, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.

Migraine, an extremely disabling neurological disorder, has a strong genetic component. Since monogenic migraines (resulting from mutations or changes in a single gene) may help researchers discover migraine pathophysiology, transgenic mice models harboring gene mutations identified in Familial Hemiplegic Migraine (FHM) patients have been generated. Studies in these FHM mutant mice models have shed light on the mechanisms of migraine and may aid in the identification of novel targets for treatment. More specifically, the studies shed light on how gene mutations, hormones, and other factors impact the pathophysiology of migraine. The models may also be of relevance to researchers outside the field of migraine as some of their aspects are relevant to pain in general. Additionally, because of the comorbidities associated with migraine, they share similarities with the mutant mouse models of epilepsy, stroke, and perhaps depression. Here, we review the experimental data obtained from these mutant mice and focus on how they can be used to investigate the pathophysiology of migraine, including synaptic plasticity, neuroinflammation, metabolite alterations, and molecular and behavioral mechanisms of pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1570159X17666190513085013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052833PMC
February 2020

Nuclear expansion and pore opening are instant signs of neuronal hypoxia and can identify poorly fixed brains.

Sci Rep 2018 10 3;8(1):14770. Epub 2018 Oct 3.

Hacettepe University, Institute of Neurological Sciences and Psychiatry, Ankara, 06100, Turkey.

The initial phase of neuronal death is not well characterized. Here, we show that expansion of the nuclear membrane without losing its integrity along with peripheralization of chromatin are immediate signs of neuronal injury. Importantly, these changes can be identified with commonly used nuclear stains and used as markers of poor perfusion-fixation. Although frozen sections are widely used, no markers are available to ensure that the observed changes were not confounded by perfusion-induced hypoxia/ischemia. Moreover, HMGB1 was immediately released and p53 translocated to mitochondria in hypoxic/ischemic neurons, whereas nuclear pore complex inhibitors prevented the nuclear changes, identifying novel neuroprotection targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-32878-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170374PMC
October 2018
-->