Aurélien Fortoul

Brain architectures vary widely across species, yet how neuronal positioning constrains the type of circuits that can be made, and their function, remains poorly understood. Here we examine how neuronal position affects molecular identity, connectivity and function by studying Eml1 knockout mice, which exhibit abnormally located (heterotopic) neurons beneath the cortex. Heterotopic neurons maintained their molecular signatures, formed appropriate long-range connections and exhibited coherent electrophysiological properties. They organized into functional sensory-processing centers that mirrored their cortical counterparts, with preserved somatotopic mapping and responsiveness to sensory stimuli. Remarkably, cortical silencing did not impair sensory discrimination, revealing that heterotopic neurons were the main drivers of this function. Hence, equivalent circuits can emerge in different spatial configurations, allowing diverse brain architectures to converge on similar functional outcomes.

Brains come in various sizes and shapes, yet how neuronal position constrains the type of circuits that they can form remains largely unknown. The spatial layout of anatomical structures with corresponding functions varies widely across species ( J - 4 ). Also, during evolution, anatomical structures have duplicated and then diverged to generate new circuits and functions ( 5 , 6 ). Thus, it is critical to understand how the position of neurons constrains their integration into circuits and, ultimately, their function. To address this question, we studied EmlJ knockout mice in which subsets of neocortical neurons form a new structure below the neocortex termed heterotopia (Ht). We examined how this new location affects the molecular identity, topography, input-output circuit connectivity, electrophysiology, and functional properties of these neurons. Our results reveal a striking conservation of the cellular features and circuit properties of Ht neurons, despite their abnormal location and misorientation. Supporting this observation, these neurons were able to functionally substitute for overlying neocortical neurons in a behaviorally relevant task when the latter were optogenetically silenced. Hence, specific neuronal identities and associated function can be reproduced in altered anatomical settings, revealing a remarkable level of self-organization and adaptability of neocortical circuits.

Grey matter heterotopia (GMH) are neurodevelopmental disorders associated with abnormal cortical function and epilepsy. Subcortical band heterotopia (SBH) and periventricular nodular heterotopia (PVNH) are two well-recognized GMH subtypes in which neurons are misplaced, either forming nodules lining the ventricles in PVNH, or forming bands in the white matter in SBH. Although both PVNH and SBH are commonly associated with epilepsy, it is unclear whether these two GMH subtypes differ in terms of pathological consequences or, on the contrary, share common altered mechanisms. Here, we studied two robust preclinical models of SBH and PVNH, and performed a systematic comparative assessment of the physiological and morphological diversity of heterotopia neurons, as well as the dynamics of epileptiform activity and input connectivity. We uncovered a complex set of altered properties, including both common and distinct physiological and morphological features across heterotopia subtypes, and associated with specific dynamics of epileptiform activity. Taken together, these results suggest that pro-epileptic circuits in GMH are, at least in part, composed of neurons with distinct, subtype-specific, physiological and morphological properties depending on the heterotopia subtype. Our work supports the notion that GMH represent a complex set of disorders, associating both shared and diverging pathological consequences, and contributing to forming epileptogenic networks with specific properties. A deeper understanding of these properties may help to refine current GMH classification schemes by identifying morpho-electric signatures of GMH subtypes, to potentially inform new treatment strategies.