# Alterations in dopaminergic innervation and receptors in focal cortical dysplasia

## TL;DR

This study shows that brain regions with focal cortical dysplasia type 2 have reduced dopamine connections and altered dopamine receptor patterns, which may contribute to epilepsy.

## Contribution

The study provides the first comprehensive analysis of dopaminergic innervation and receptor expression in human FCD type 2 and a mouse model.

## Key findings

- Human FCD type 2 areas show decreased dopaminergic innervation density compared to control areas.
- Dopamine receptors 1 and 2 are differentially expressed in dysmorphic neurons in FCD type 2.
- Altered lamination patterns of dopaminergic innervation are observed in FCD type 2 regions.

## Abstract

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.

Focal cortical dysplasia (FCD) type 2 is one of the most common malformations of cortical development associated with treatment-resistant epilepsy. Using human FCD type 2 biopsies and a mouse model, Meli et al. show that affected brain regions exhibit reduced dopaminergic innervation and altered patterns of dopamine receptor expression.