Investigating the Molecular identity of PAcemaker neurons in CorTical development

Project Information

IMPACT

Grant agreement ID: 101043003

DOI

10.3030/101043003

EC signature date 4 February 2022

Start date 1 September 2022

End date 31 August 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 490 000,00

EU contribution

€ 1 490 000,00

Coordinated by

UNIVERSITA HUMANITAS
Italy

Periodic Reporting for period 1 - IMPACT (Investigating the Molecular identity of PAcemaker neurons in CorTical development)

Reporting period: 2022-09-01 to 2025-02-28

Summary of the context and overall objectives of the project

The IMPACT project investigates spontaneous neuronal activity in the developing brain, with a focus on pacemaker neurons, which regulate early brain activity critical for the formation of neural circuits. Understanding how different neurons in the cerebral cortex contribute to early spontaneous electrical rhythms is vital for unraveling the molecular mechanisms behind brain development and the emergence of neurological disorders in newborns. Central to the project is the study of HCN1, an ion channel protein that modulates pacemaker neuron activity. This research aims to bridge gaps in our knowledge of neuronal diversity and functions during brain development, with potential applications in treating conditions such as infantile epilepsy and complications from preterm birth. By linking these scientific findings to observable outcomes like sleep cycles and motor skills, the project also aims to explore how disruptions in early brain activity can influence brain circuits and behavior.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Over the course of the project, significant progress was made in understanding the molecular mechanisms that govern neuronal communication, particularly the role of ion channels in neuronal development and fate acquisition. We identified distinct ion channel profiles for different neuronal subtypes in the cerebral cortex, shedding light on how specific combinations might influence neuronal activity during early phases of development. This research is crucial for understanding brain circuit development and how disruptions in these processes can lead to neurological disorders. We also studied the role of the HCN1 protein, using genetically modified mice, to explore its influence on brain cell communication and circuit formation, highlighting its potential as a target for therapies aimed at treating brain disorders such as infantile epilepsy and autism. Additionally, the use of advanced method to analyze individual neurons' genetic makeup and activity in real-time has provided new tools to improve our understanding of brain function and disease mechanisms.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our project has uncovered several results that expand the current understanding of brain development and neuronal function. In particular, we identified that Hcn1 plays a crucial role in early neuronal activity, and its absence leads to significant structural and functional changes related to cortical neuron identity. This discovery opens up new avenues for therapeutic strategies targeting ion channels, particularly for neurodevelopmental disorders like infantile epilepsy and autism. Furthermore, our research has led to the implementation of innovative methodologies that allow for precise analysis of neuronal activity and molecular processes. These advancements not only push the boundaries of developmental neuroscience but also lay the groundwork for personalized medicine approaches. To maximize the impact of these findings, further research is required to demonstrate the clinical applicability of our discoveries. Testing Hcn1 modulation in preclinical disease models will be essential for translating our results into viable therapeutic strategies.

Layer 5 cortical neurons