Research team

Expertise

The overall aim of our group is to understand how neuronal circuits form early in development, as well as the processes that lead to malfunction of these circuits or degeneration later in life. A recent focus are the basal ganglia; a network of interconnected subcortical nuclei important for cognition and motor control.

Unraveling the role and contribution of neurons and microglia to the neurodevelopmental problems seen in children with KCNQ3 gain-of-function encephalopathy. 01/02/2023 - 31/01/2025

Abstract

Kv7.2 and Kv7.3 subunits, encoded by KCNQ2 and KCNQ3, form homo- or hetero-tetrameric voltage-gated potassium channels (Kv7 channel). Kv7 channels expressed in neurons produce a well characterized M-current that is a critical regulator of neuronal excitability by dampening repetitive firing. Gain-of-function (GoF) variants in KCNQ2 and KCNQ3 lead to severe early-onset neurodevelopmental disorders (KCNQ2- and KCNQ3-GoF-Encephalopathy). However, autism spectrum disorder (ASD) is a much more prominent feature in KCNQ3-GoF-Encephalopathy. This suggests for a Kv7.3 unique function during neurodevelopment. Interestingly, single nuclei RNA sequencing databases have revealed that KCNQ3 is the only KCNQ gene that is highly expressed in microglia in the human brain. Given the emerging evidence that microglia dysfunction is involved in the development of NDD and ASD, we hypothesize that KCNQ3-GoF variants affect microglia function which contributes to the already dysfunctional neuronal network. In this project, I will build a human tripartite neuronal-microglia model (excitatory neurons, inhibitory neurons and microglia) derived from induced pluripotent stem cells that carry KCNQ-GoF variants, as well as control lines. With this model I will (i) investigate the function of Kv7.3 in microglia and (ii) unravel the contribution of each cell type to KCNQ3-GoF-Encephalopthy. Furthermore, this model will be used as a screening platform to perform a proof-of-concept study for RNA interference using antisense oligonucleotides as a targeted treatment strategy for KCNQ3-GoF-Encephalopathy. When successful, this approach could be extended to other types of neurodevelopmental disorders and drug screenings.

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  • Research Project

Elucidating the roles for embryonic neural progenitor diversity in the formation and function of mature striatal neuronal circuits. 01/01/2023 - 31/12/2026

Abstract

Specialised cells in the embryonic brain, termed neural progenitors, give rise to all mature neurons, including those found in the striatum, a brain region critical in controlling our movements and many cognitive behaviours. These progenitor cells come in many shapes and sizes, and it remains unclear why so many different types exist, and importantly how they relate to the neurons and neural circuits found in the adult brain. This is a fundamental question and important also from a clinical perspective as alterations in embryonic progenitors are implicated in the emergence of various neurological disorders. This proposal capitalises on our ability to label distinct embryonic progenitor types and all their neurons, and firstly aims to elucidate the genes and proteins that are expressed in these mature neurons as to facilitate their classification, as well to trace their connections with other neurons in the brain. Secondly, it aims to characterise the electrical properties of these connections with a focus on those coming from an important brain region, named the thalamus, and through manipulations and behavioural studies reveal how these progenitor-derived neural circuits control movement and cognition. Together, this will provide fundamental insights into the origin of the brain's complexity, by uncovering how embryonic progenitors shape the functional identity of mature striatal neurons and opens avenues for future studies of their roles in striatal disorders.

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  • Research Project

Het begrijpen van hersencircuits vanuit de oorsprong van neuronale embryonale progenitors. 01/10/2022 - 30/09/2026

Abstract

The brain's ability to process information and guide behaviour is reliant on diverse neurons forming complex neuronal circuits. In this PhD project proposal, we set out to explore how such diversity in neurons and synaptic circuits arises with a focus on embryonic progenitor origin and using mouse as a model organism. Recently data from my lab and others suggest that key aspects of neuronal identity and synaptic specificity in both cortex and striatum are controlled by their embryonic progenitor origin. In this proposal we will explore this further and focus on the striatum, but the tools and approaches generated will be universally applicable. The PhD project proposal has four main Objectives. Firstly, we will use RNA sequencing approaches to genetically parse the different embryonic progenitors that generate striatal spiny projection neurons (SPNs) and generate tools for their fate mapping from embryo to adulthood. Secondly, we will use a variety of techniques on adult SPNs to determine what 'types' of neurons arise from different progenitor pools. Thirdly, we will use novel viral tracing approaches to observe the synaptic integration of striatal SPNs within larger brain circuits. Lastly, we will reveal the molecular recognition systems that different embryonic progenitor-derived SPNs employ to achieve synapse specificity within these larger circuits. Together they will provide new insights how the vast complexity of neurons and circuits in the striatum arises and open avenues for future study of the roles for embryonic progenitor origin in neurological and neurodevelopmental disorders.

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  • Research Project

Towards therapies for epilepsy: Probing the potential of NMDA receptor allosteric modulation. 01/04/2022 - 31/03/2023

Abstract

Epilepsy is one of the most debilitating brain disorders and to date there is a shortage of drugs to combat it effectively. This is in part the result of the complexity of epileptic seizures, which arise from interactions amongst diverse excitatory and inhibitory neurons expressing numerous ion channels and receptors as well as relevant models. Here we propose to establish two in vitro models of seizure activity, based on mouse hippocampal brain slices and neurons derived from human induced pluripotent stem cells, to investigate the efficacy of novel modulators at one key brain receptor - the glutamatergic NMDA receptor – in controlling seizure activity. In this pilot project we will investigate both positive and negative allosteric NMDA receptor modulators using a combination of electrophysiological techniques including field potential recordings, multi-neuron patch-clamp electrophysiology and multi-electrode array recordings to understand the locus of action of these drugs at the excitatory and inhibitory neurons of the brain and their ability to control seizure activity. This will allow a deeper appreciation of the balance of excitation and inhibition in the generation of seizure activity, reveal the potential of allosteric modulation in controlling seizures and provide the preliminary data for future grant applications to study their effect in vivo.

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  • Research Project

Support maintenance scientific equipment (ENU). 01/01/2022 - 31/12/2022

Abstract

Financial support towards maintenance of scientific equipment in the Experimental Neurobiology Unit (ENU). This includes various electrophysiological setups, behavioural setups, molecular biolology setups and EEG equipment amongst others.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project