Martijn Selten
Verified @kcl.ac.uk
King's College London
RESEARCH, TEACHING, or OTHER INTERESTS
Neuroscience
Scopus Publications
- A postnatal molecular switch drives activity-dependent maturation of parvalbumin interneurons
Monika Moissidis, Leyla Abbasova, Martijn Selten, Rafael Alis, Clémence Bernard, Yaiza Domínguez-Canterla, Fazal Oozeer, Shenyue Qin, Audrey Kelly, Laura Mòdol, Navneet A. Vasistha, Benjamin Jones, Pawan Dhami, Konstantin Khodosevich, Fursham Hamid, Paul Lavender, Nuria Flames, Oscar Marín
Cell, 2025
Cortical neurons are specified during embryonic development but often acquire their mature properties at relatively late stages of postnatal development. This delay in terminal differentiation is particularly prominent for fast-spiking parvalbumin-expressing (PV + ) interneurons, which play critical roles in regulating the function of the cerebral cortex. We found that the maturation of PV + interneurons is triggered by neuronal activity and mediated by the transcriptional cofactor peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α). Developmental loss of PGC-1α prevents PV + interneurons from acquiring unique structural, electrophysiological, synaptic, and metabolic features and disrupts their diversification into distinct subtypes. PGC-1α functions as a master regulator of the differentiation of PV + interneurons by directly controlling gene expression through a transcriptional complex that includes ERRγ and Mef2c transcription factors. Our results uncover a molecular switch that translates neural activity into a specific transcriptional program, promoting the maturation of PV + interneurons at the appropriate developmental stage. - Regulation of PV interneuron plasticity by neuropeptide-encoding genes
Martijn Selten, Clémence Bernard, Diptendu Mukherjee, Fursham Hamid, Alicia Hanusz-Godoy, Fazal Oozeer, Christoph Zimmer, Oscar Marín
Nature, 2025
Neuronal activity must be regulated in a narrow permissive band for the proper operation of neural networks. Changes in synaptic connectivity and network activity—for example, during learning—might disturb this balance, eliciting compensatory mechanisms to maintain network function1–3. In the neocortex, excitatory pyramidal cells and inhibitory interneurons exhibit robust forms of stabilizing plasticity. However, although neuronal plasticity has been thoroughly studied in pyramidal cells4–8, little is known about how interneurons adapt to persistent changes in their activity. Here we describe a critical cellular process through which cortical parvalbumin-expressing (PV+) interneurons adapt to changes in their activity levels. We found that changes in the activity of individual PV+ interneurons drive bidirectional compensatory adjustments of the number and strength of inhibitory synapses received by these cells, specifically from other PV+ interneurons. High-throughput profiling of ribosome-associated mRNA revealed that increasing the activity of a PV+ interneuron leads to upregulation of two genes encoding multiple secreted neuropeptides: Vgf and Scg2. Functional experiments demonstrated that VGF is critically required for the activity-dependent scaling of inhibitory PV+ synapses onto PV+ interneurons. Our findings reveal an instructive role for neuropeptide-encoding genes in regulating synaptic connections among PV+ interneurons in the adult mouse neocortex. - Somatostatin interneurons control the timing of developmental desynchronization in cortical networks
Laura Mòdol, Monika Moissidis, Martijn Selten, Fazal Oozeer, Oscar Marín
Neuron, 2024
Synchronous neuronal activity is a hallmark of the developing brain. In the mouse cerebral cortex, activity decorrelates during the second week of postnatal development, progressively acquiring the characteristic sparse pattern underlying the integration of sensory information. The maturation of inhibition seems critical for this process, but the interneurons involved in this crucial transition of network activity in the developing cortex remain unknown. Using in vivo longitudinal two-photon calcium imaging during the period that precedes the change from highly synchronous to decorrelated activity, we identify somatostatin-expressing (SST+) interneurons as critical modulators of this switch in mice. Modulation of the activity of SST+ cells accelerates or delays the decorrelation of cortical network activity, a process that involves regulating the maturation of parvalbumin-expressing (PV+) interneurons. SST+ cells critically link sensory inputs with local circuits, controlling the neural dynamics in the developing cortex while modulating the integration of other interneurons into nascent cortical circuits. - Cortical wiring by synapse type–specific control of local protein synthesis
Clémence Bernard, David Exposito-Alonso, Martijn Selten, Stella Sanalidou, Alicia Hanusz-Godoy, Alfonso Aguilera, Fursham Hamid, Fazal Oozeer, Patricia Maeso, Leanne Allison, Matthew Russell, Roland A. Fleck, Beatriz Rico, Oscar Marín
Science, 2022
Neurons use local protein synthesis to support their morphological complexity, which requires independent control across multiple subcellular compartments up to the level of individual synapses. We identify a signaling pathway that regulates the local synthesis of proteins required to form excitatory synapses on parvalbumin-expressing (PV + ) interneurons in the mouse cerebral cortex. This process involves regulation of the TSC subunit 2 (Tsc2) by the Erb-B2 receptor tyrosine kinase 4 (ErbB4), which enables local control of messenger RNA {mRNA} translation in a cell type–specific and synapse type–specific manner. Ribosome-associated mRNA profiling reveals a molecular program of synaptic proteins downstream of ErbB4 signaling required to form excitatory inputs on PV + interneurons. Thus, specific connections use local protein synthesis to control synapse formation in the nervous system. - Serotonergic regulation of bipolar cell survival in the developing cerebral cortex
Fong Kuan Wong, Martijn Selten, Claudia Rosés-Novella, Varun Sreenivasan, Noemí Pallas-Bazarra, Eleni Serafeimidou-Pouliou, Alicia Hanusz-Godoy, Fazal Oozeer, Robert Edwards, Oscar Marín
Cell Reports, 2022
One key factor underlying the functional balance of cortical networks is the ratio of excitatory and inhibitory neurons. The mechanisms controlling the ultimate number of interneurons are beginning to be elucidated, but to what extent similar principles govern the survival of the large diversity of cortical inhibitory cells remains to be investigated. Here, we investigate the mechanisms regulating developmental cell death in neurogliaform cells, bipolar cells, and basket cells, the three main populations of interneurons originating from the caudal ganglionic eminence and the preoptic region. We found that all three subclasses of interneurons undergo activity-dependent programmed cell death. However, while neurogliaform cells and basket cells require glutamatergic transmission to survive, the final number of bipolar cells is instead modulated by serotonergic signaling. Together, our results demonstrate that input-specific modulation of neuronal activity controls the survival of cortical interneurons during the critical period of programmed cell death. - Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks
Britt Mossink, Jon-Ruben van Rhijn, Shan Wang, Katrin Linda, Maria R. Vitale, Johanna E. M. Zöller, Eline J. H. van Hugte, Jitske Bak, Anouk H. A. Verboven, Martijn Selten, Moritz Negwer, Brooke L. Latour, Ilse van der Werf, Jason M. Keller, Teun M. Klein Gunnewiek, Chantal Schoenmaker, Astrid Oudakker, Alessia Anania, Sophie Jansen, Klaus-Peter Lesch, Monica Frega, Hans van Bokhoven, Dirk Schubert, Nael Nadif Kasri
Molecular Psychiatry, 2022
Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations.Cadherin-13(CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance. - Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype
Monica Frega, Martijn Selten, Britt Mossink, Jason M. Keller, Katrin Linda, Rebecca Moerschen, Jieqiong Qu, Pierre Koerner, Sophie Jansen, Astrid Oudakker, Tjitske Kleefstra, Hans van Bokhoven, Huiqing Zhou, Dirk Schubert, Nael Nadif Kasri
Cell Reports, 2020
Pathogenic mutations in either one of the epigenetic modifiers EHMT1, MBD5, MLL3, or SMARCB1 have been identified to be causative for Kleefstra syndrome spectrum (KSS), a neurodevelopmental disorder with clinical features of both intellectual disability (ID) and autism spectrum disorder (ASD). To understand how these variants lead to the phenotypic convergence in KSS, we employ a loss-of-function approach to assess neuronal network development at the molecular, single-cell, and network activity level. KSS-gene-deficient neuronal networks all develop into hyperactive networks with altered network organization and excitatory-inhibitory balance. Interestingly, even though transcriptional data reveal distinct regulatory mechanisms, KSS target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS genes mainly converge at the level of neuronal network communication, providing insights into the pathophysiology of KSS and phenotypically congruent disorders. - Optimization of interneuron function by direct coupling of cell migration and axonal targeting
Lynette Lim, Janelle M. P. Pakan, Martijn M. Selten, André Marques-Smith, Alfredo Llorca, Sung Eun Bae, Nathalie L. Rochefort, Oscar Marín
Nature Neuroscience, 2018 - Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse
D C Ung, G Iacono, H Méziane, E Blanchard, M-A Papon, M Selten, J-R van Rhijn, R Montjean, J Rucci, S Martin, A Fleet, M-C Birling, S Marouillat, R Roepman, M Selloum, A Lux, R-A Thépault, P Hamel, K Mittal, J B Vincent, O Dorseuil, H G Stunnenberg, P Billuart, N Nadif Kasri, Y Hérault, F Laumonnier
Molecular Psychiatry, 2018
Synapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1−/y) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction. - Inhibitory control of the excitatory/inhibitory balance in psychiatric disorders
Martijn Selten, Hans van Bokhoven, Nael Nadif Kasri
F1000research, 2018
Neuronal networks consist of different types of neurons that all play their own role in order to maintain proper network function. The two main types of neurons segregate in excitatory and inhibitory neurons, which together regulate the flow of information through the network. It has been proposed that changes in the relative strength in these two opposing forces underlie the symptoms observed in psychiatric disorders, including autism and schizophrenia. Here, we review the role of alterations to the function of the inhibitory system as a cause of psychiatric disorders. First, we explore both patient and post-mortem evidence of inhibitory deficiency. We then discuss the function of different interneuron subtypes in the network and focus on the central role of a specific class of inhibitory neurons, parvalbumin-positive interneurons. Finally, we discuss genes known to be affected in different disorders and the effects that mutations in these genes have on the inhibitory system in cortex and hippocampus. We conclude that alterations to the inhibitory system are consistently identified in animal models of psychiatric disorders and, more specifically, that mutations affecting the function of parvalbumin-positive interneurons seem to play a central role in the symptoms observed in these disorders. - Reduced inhibition within layer IV of sert knockout rat barrel cortex is associated with faster sensory integration
Stéphanie Miceli, Nael Nadif Kasri, Joep Joosten, Chao Huang, Lara Kepser, Rémi Proville, Martijn M. Selten, Fenneke van Eijs, Alireza Azarfar, Judith R. Homberg, Tansu Celikel, Dirk Schubert
Cerebral Cortex, 2017 - Increased GABA B receptor signaling in a rat model for schizophrenia
Martijn M. Selten, Francisca Meyer, Wei Ba, Astrid Vallès, Dorien A. Maas, Moritz Negwer, Vivian D. Eijsink, Ruben W. M. van Vugt, Josephus A. van Hulten, Nick H. M. van Bakel, Joey Roosen, Robert J. van der Linden, Dirk Schubert, Michel M. M. Verheij, Nael Nadif Kasri, Gerard J. M. Martens
Scientific Reports, 2016 - Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling
Marco Benevento, Giovanni Iacono, Martijn Selten, Wei Ba, Astrid Oudakker, Monica Frega, Jason Keller, Roberta Mancini, Elly Lewerissa, Tjitske Kleefstra, Henk G. Stunnenberg, Huiqing Zhou, Hans van Bokhoven, Nael Nadif Kasri
Neuron, 2016 - ARHGAP12 Functions as a Developmental Brake on Excitatory Synapse Function
W. Ba, M.M. Selten, J. van der Raadt, H. van Veen, L.-L. Li, M. Benevento, A.R. Oudakker, R.S.E. Lasabuda, S.J. Letteboer, R. Roepman, R.J.A. van Wezel, M.J. Courtney, H. van Bokhoven, N. Nadif Kasri
Cell Reports, 2016 - Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition
O Rivero, M M Selten, S Sich, S Popp, L Bacmeister, E Amendola, M Negwer, D Schubert, F Proft, D Kiser, A G Schmitt, C Gross, S M Kolk, T Strekalova, D van den Hove, T J Resink, N Nadif Kasri, K P Lesch
Translational Psychiatry, 2015 - Pituitary melanotrope cells of Xenopus laevis are of neural ridge origin and do not require induction by the infundibulum
Gerald W. Eagleson, Martijn M. Selten, Eric W. Roubos, Bruce G. Jenks
General and Comparative Endocrinology, 2012
