Information

CEREBRAL CORTICAL DEVELOPMENT GROUP

Zoltán Molnár MD DPhil

University Lecturer
Tel.: 01865 272169
Fax: 01865 272420
Email: zoltan.molnar@anat.ox.ac.uk

1. Background of our research

The billions of cells and trillions of connections of the human brain are generated from the complex interactions between our unfolding genetic program and our environment. It is a miracle how the activation of sets of our 20-30 000 genes in different combination and sequence can produce the most complex object in our known universe. Development is the ultimate readout of our genome; combination of genetic susceptibility and environmental perturbations could lead to several devastating diseases like neural tube closure defects, schizophrenia, autism and attention deficit disorder. The construction of the brain follows an integrated series of developmental steps. It begins with the decision of a few early embryonic cells to become neural progenitors, and then the neural plate will form the neural tube, which will differentiate further using signals outside and within the neural tissue. As connections form between nerve cells and their electrical properties emerge, the brain begins to process information and mediate behaviours even during the embryonic life. Some of the underlying circuitry is built into the nervous system during embryogenesis. However, interactions with the world continuously update and adapt the brain’s functional architecture. The mechanisms by which these plastic changes occur appear to be a continuation of the process that sculpts the brain during development. To understand the brain and its devastating diseases, we need to reveal the mechanisms that produce it and the ways in which it can constantly change throughout lifetime.

The principal neuronal types of the cerebral cortex are the excitatory pyramidal cells, which project to distant targets, and the inhibitory nonpyramidal cells, which are the cortical interneurons. Pyramidal neurons are generated in the cortical neuroepithelium and migrate radially to reach the cortex following an inside-outside gradient (Rakic, 1995). In rodent, only a few nonpyramidal cells are generated in the cortical ventricular zone. It was recently established that cells of the pallidum also contribute to the formation of the cerebral cortex with interneurons. These cells migrate tangentially through the striatocortical junction to reach the cortex.

Cortical areas do not appear to be fully pre-programmed and differences arise by local interactions with afferent neurons. Thalamic axons, which later will mediate most sensory information from the environment, reach the cortex at a very early stage, before the majority of cortical neurons have even been born. Recent work points to the crucial role of the early-developing thalamocortical projections and their interactions with the developing cortical circuitry in establishing some aspects of the functional and structural organization of the cortex. Nevertheless some aspects of cortical specialisation do not require thalamic input.

Schizophrenia is a severe brain disorder that afflicts approximately 1% of the population and produces a lifetime of disability and cost within the UK estimated at £2.6 billion a year. However, the specific factors that give rise to the illness remain elusive. The most consistent hypothesis suggests that schizophrenia maybe a consequence of a genetic abnormality, i.e., a mutation in susceptibility genes that act on early stages of neurodevelopment and environmental events during pregnancy or postnatal period (Lewis and Levitt, 2002).

Research Programme

We cover several topics or areas related to cerebral cortical development.

A: Cerebral Cortical Cell fate determination: We examine the cerebral cortical cell generation and early differentiation. We study two particular systems: subplate cells and layer 5 projection neurons.
B: Migration of cortical neurons and migration disorders: We are interested in the molecular and cellular mechanisms of cortical cell migration. Compare and contrast the radial versus tangential migration patterns and investigate the possible links with human migration disorders. We are particularly interested in the comparative aspects of interneuron generation and migration in reptiles and in examining the differences between primates and rodents.
C: Cortical arealisation: We are studying the signaling mechanisms that set the coordinates for the further establishment of cortical areas. There are human pathologies (including congenital bilateral frontoparietal polymicrogyria syndromes) where regional differences are striking and basic research is needed for further understanding.
D: Genes in connectivity: There are several genes implicated in the development of cortical connectivity. We are particularly interested in the cellular and molecular mechanisms involved in the cortico-cortical and thalamocortical connectivity. We hope to relate these mechanisms to human pathologies (Schizophrenia, Synesthesia).
F: Susceptibility genes of cognitive disorders. Combinations of genetic susceptibility and environmental perturbations are thought to be responsible for the diseases of: schizophrenia, autism, dyslexia, and attention deficit disorders. This field faces difficulties because no single gene or factor is responsible for driving a highly complex biological process. We are very interested in understanding the function of various susceptibility genes (Snap25, Munc18).

Current Funding:

MRC, Wellcome Trust, HFSP, EU

Other Activities: Fellow, St John's College; Lecturer, St Hilda's College; Associate of Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne, Switzerland; Receiving Editor of European Journal of Neuroscience.

Key Publications

Jones L, López-Bendito G, Gruss P, Stoykova A, Molnár Z (2002) Pax6 is required for the normal development of the forebrain axonal connections. Development 129:5041-52.

Molnár Z, López-Bendito G, Small J, Partridge LD, Blakemore C, Wilson MC, (2002) Normal development of embryonic thalamocortical connectivity in the absence of evoked synaptic activity. J. Neurosci 22:10313-23.

López-Bendito G and Molnár Z (2003) Thalamocortical Development: How are we going to get there? Nature Reviews Neuroscience 4: 276-289.

López-Bendito G, Luján R, Shigemoto R, Ganter P, Paulsen O, Molnár Z (2003) Blockade of GABAB receptors alters the tangential migration of neurons. Cerebral Cortex 13(9):932-942.

Voelker CCJ, Garin N, Taylor JSH., Gahwiler BH, Hornung J-P, Molnár Z (2004) Selective Neurofilament (SMI-32, FNP-7 and N200) Expression in subpopulations of layer 5 pyramidal neurons in vivo and in vitro. Cerebral Cortex 14(11):1276-86.

Higashi S, Hioki K, Kurotani T and Molnár Z (2005) Functional thalamocortical synapse reorganization from subplate to layer IV during postnatal development in the reeler-like mutant : an optical recording study. J. Neuroscience 25(6):1395-406.

Molnár Z and Cheung A.F.P. (2006) Towards the classification of subpopulations of layer V pyramidal projection neurons. Neuroscience Research 55(2):105-115.

Bystron I, Rakic P, Molnár Z, Blakemore C (2006) The first neurons of the human cerebral cortex. Nature Neuroscience (in press, July issue).

1: More publications can be found here (after 2000).
2: More publications can be found here (before 2000).
3: Books, book chapters and letters here

Main Collaborators:

Ole Paulsen, University Laboratory of Physiology, Oxford
Jeremy Taylor, Department of Human Anatomy and Genetics
Kay Davies, Department of Human Anatomy and Genetics, Oxford
Paul Harrison, Dr Sharon Eastwood (supported by MRC)
Colin Blakemore and Irina Bystron, University Laboratory of Physiology, Oxford
John Parnavelas, University College London, UK

HFSP Consortium, supported from a Research Grant from the Human Frontiers Science Program Organization (2002-2005):
Etienne Audinat, Laboratoire de Neurophysiologie, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Ecole Superiore de Physique et Chimie Industrielles, Paris, France.
Nobuhiko Yamamoto, University of Osaka, Osaka, Japan
Daniel Lavery, Purdue Pharma LP, Cranbury NJ, USA

Members of the EU Consortium on Cortical Development (CONCORDE )
Previously supported by European Commission-Biomed Grant (QLRT-1999-30158) - 2000-2004
André Goffinet (Brussels) Colette Dehay and Henry Kennedy (Lyon), Christine Métin (Paris), Egbert Welker (Lausanne), Michael Frotcher (Freiburgh), Anastassia Stoykova (Goettingen), Antonello Mallamaci (Milan), Gundela Meyer (La Laguna), David Price (Edinburgh); John Parnavelas (London).

Henry Kennedy and Colette Dehay INSERM U371, Lyon, France, supported by Alliance - Franco-British research partnership programme, British Council.

Dr Shuji Higashi and Professor Keisuke Toyama, Kyoto Prefectural School of Medicine, Kyoto, Japan
Professor Beat Gähwiler, Brain Research Institut, University of Zürich, Switzerland
Professor Leah Krubitzer, Center for Neuroscience, University of California, Davis, USA
Professor Alessandro Vercelli, Department of Human Anatomy, University of Turin, Torino, Italy

Group Members

Mr Dan Blakey – Wellcome Trust Graduate Student
Dr Amanda Cheung – MRC Postdoctoral Fellow
Mr Jamin DeProto – Clarendon Award, Graduate Student
Miss Anna Hoerder – Wellcome Trust Graduate Student (jointly with Ole Paulsen)
Dr Pinon Carmen – MRC Postdoctoral Fellow
Dr Wei-Zhi Wang – Wellcome Trust Postdoctoral Fellow
Dr Peng Zhou – visiting scientist (jointly with Professor Morris)
Mr Alexander Pollen – Wellcome Trust MSc in Neuroscience Project Student
Mr Thomas Lickiss – Wellcome Trust MSc in Neuroscience Project Student
Mr Daniel Stubbs (SJC) FHS Dissertation Student
Mr Ankeet Jethwa (BAL) FHS Dissertation Student
Miss Vildane Berani (MER) FHS Disseretation Student

Associate members:
Dr Irina Bystron – Sherrington Building, Department of Physiology, Anatomy and Genetics
Dr Sharon Eastwood – Warneford Hospital, Oxford – Prof Paul Harrison’s Group

Alumni :

a list of Alumni can be seen here