TY  - JOUR
AU  - Meli, Norisa
AU  - Sheran, Katherine
AU  - Pitsch, Julika
AU  - Krabbe, Sabine
AU  - Borger, Valeri
AU  - Baumgartner, Tobias
AU  - Becker, Albert
AU  - Blaess, Sandra
TI  - Alterations in dopaminergic innervation and receptors in focal cortical dysplasia.
JO  - Brain
VL  - 148
IS  - 8
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2025-00911
SP  - 2899 - 2911
PY  - 2025
AB  - Focal 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.
KW  - Humans
KW  - Animals
KW  - Mice
KW  - Male
KW  - Female
KW  - Malformations of Cortical Development, Group I: pathology
KW  - Malformations of Cortical Development, Group I: metabolism
KW  - Adult
KW  - Adolescent
KW  - Prefrontal Cortex: metabolism
KW  - Prefrontal Cortex: pathology
KW  - Disease Models, Animal
KW  - Young Adult
KW  - Receptors, Dopamine: metabolism
KW  - Middle Aged
KW  - Dopaminergic Neurons: metabolism
KW  - Dopaminergic Neurons: pathology
KW  - Child
KW  - Malformations of Cortical Development: pathology
KW  - Malformations of Cortical Development: metabolism
KW  - TOR Serine-Threonine Kinases: metabolism
KW  - TOR Serine-Threonine Kinases: genetics
KW  - Focal Cortical Dysplasia
KW  - Epilepsy
KW  - cortical malformations (Other)
KW  - epileptogenesis (Other)
KW  - neurodevelopmental disorders (Other)
KW  - neuromodulation (Other)
KW  - neurotransmitter systems (Other)
KW  - Receptors, Dopamine (NLM Chemicals)
KW  - TOR Serine-Threonine Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40235315
C2  - pmc:PMC12316006
DO  - DOI:10.1093/brain/awaf080
UR  - https://pub.dzne.de/record/280233
ER  -