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000280233 005__ 20250824001755.0
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000280233 037__ $$aDZNE-2025-00911
000280233 041__ $$aEnglish
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000280233 1001_ $$aMeli, Norisa$$b0
000280233 245__ $$aAlterations in dopaminergic innervation and receptors in focal cortical dysplasia.
000280233 260__ $$aOxford$$bOxford Univ. Press$$c2025
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000280233 520__ $$aFocal cortical dysplasia (FCD) type 2 is the most common malformation of cortical development associated with pharmaco-resistant focal epilepsy and frequently located in the frontal cortex. Neuropathological hallmarks comprise abnormal cortical layering and enlarged, dysmorphic neuronal elements. Fundamentally altered local neuronal activity has been reported in human FCD type 2 epilepsy surgical biopsies. Of note, FCD type 2 emerges during brain development and forms complex connectivity architectures with surrounding neuronal networks. Local cortical microcircuits, particularly in frontal localization, are extensively modulated by monoaminergic axonal projections originating from the brainstem. Previous analysis of monoaminergic modulatory inputs in human FCD type 2 biopsies suggested altered density and distribution of these monoaminergic axons; however, a systematic investigation is still pending. Here, we perform a comprehensive analysis of dopaminergic (DA) innervation, in human FCD type 2 biopsies and in the medial prefrontal cortex (mPFC) of an FCD type 2 mouse model [mechanistic target of rapamyin (mTOR) hyperactivation model] during adolescent and adult stages. In addition, we analyse the expression of dopamine receptor transcripts via multiplex fluorescent RNA in situ hybridization in human specimens and the mPFC of this mouse model. In the mTOR hyperactivation mouse model, we observe a transient alteration of DA innervation density during adolescence and a trend towards decreased innervation in adulthood. In human FCD type 2 areas, the overall DA innervation density is decreased in adult patients compared with control areas from these patients. Moreover, the DA innervation shows an altered lamination pattern in the FCD type 2 area compared with the control area. Dopamine receptors 1 and 2 appear to be differentially expressed in the dysmorphic neurons in human samples and mTOR-mutant cells in mice compared with normally developed neurons. Intriguingly, our results suggest complex molecular and structural alterations putatively inducing impaired DA neurotransmission in FCD type 2. We hypothesize that this may have important implications for the development of these malformations and the manifestation of seizures.
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000280233 650_7 $$2Other$$acortical malformations
000280233 650_7 $$2Other$$aepileptogenesis
000280233 650_7 $$2Other$$aneurodevelopmental disorders
000280233 650_7 $$2Other$$aneuromodulation
000280233 650_7 $$2Other$$aneurotransmitter systems
000280233 650_7 $$2NLM Chemicals$$aReceptors, Dopamine
000280233 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aTOR Serine-Threonine Kinases
000280233 650_2 $$2MeSH$$aHumans
000280233 650_2 $$2MeSH$$aAnimals
000280233 650_2 $$2MeSH$$aMice
000280233 650_2 $$2MeSH$$aMale
000280233 650_2 $$2MeSH$$aFemale
000280233 650_2 $$2MeSH$$aMalformations of Cortical Development, Group I: pathology
000280233 650_2 $$2MeSH$$aMalformations of Cortical Development, Group I: metabolism
000280233 650_2 $$2MeSH$$aAdult
000280233 650_2 $$2MeSH$$aAdolescent
000280233 650_2 $$2MeSH$$aPrefrontal Cortex: metabolism
000280233 650_2 $$2MeSH$$aPrefrontal Cortex: pathology
000280233 650_2 $$2MeSH$$aDisease Models, Animal
000280233 650_2 $$2MeSH$$aYoung Adult
000280233 650_2 $$2MeSH$$aReceptors, Dopamine: metabolism
000280233 650_2 $$2MeSH$$aMiddle Aged
000280233 650_2 $$2MeSH$$aDopaminergic Neurons: metabolism
000280233 650_2 $$2MeSH$$aDopaminergic Neurons: pathology
000280233 650_2 $$2MeSH$$aChild
000280233 650_2 $$2MeSH$$aMalformations of Cortical Development: pathology
000280233 650_2 $$2MeSH$$aMalformations of Cortical Development: metabolism
000280233 650_2 $$2MeSH$$aTOR Serine-Threonine Kinases: metabolism
000280233 650_2 $$2MeSH$$aTOR Serine-Threonine Kinases: genetics
000280233 650_2 $$2MeSH$$aFocal Cortical Dysplasia
000280233 650_2 $$2MeSH$$aEpilepsy
000280233 7001_ $$0P:(DE-2719)9001413$$aSheran, Katherine$$b1$$udzne
000280233 7001_ $$aPitsch, Julika$$b2
000280233 7001_ $$0P:(DE-2719)9001056$$aKrabbe, Sabine$$b3$$udzne
000280233 7001_ $$aBorger, Valeri$$b4
000280233 7001_ $$aBaumgartner, Tobias$$b5
000280233 7001_ $$aBecker, Albert$$b6
000280233 7001_ $$00000-0002-1898-4891$$aBlaess, Sandra$$b7
000280233 773__ $$0PERI:(DE-600)1474117-9$$a10.1093/brain/awaf080$$gVol. 148, no. 8, p. 2899 - 2911$$n8$$p2899 - 2911$$tBrain$$v148$$x0006-8950$$y2025
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