The goal of Dr. Martínez-Cerdeño's laboratory is to determine the etiology and the pathology of some forms of autism. In addition, we study the role of stem cells in the development, evolution, and pathogenesis of the mammalian cerebral cortex. We study the anatomy and pathology of autism and related diseases in postmortem brains and based on our finding we develop animal models for autism research. Animal model mimicking our findings in human provide an excellent tool to generate and test new treatment for different kinds of autism.


AUTISM ANATOMY AND PATHOLOGY

Our lab focuses on unraveling the pathology of autism. We investigate the anatomy, pathology and histology of postmortem tissue from subjects with autism and related disorders, such as Fragile X syndrome. Our most recent discovery is that a distinct parvalbumin-expressing interneuron, the Chandelier cell, is reduced in discrete areas of the prefrontal cortex in autism. This discovery suggests that a deficit of inhibition acting on pyramidal neurons contributes to the cognitive phenotype of autism. This brings us a step closer to a fuller understanding of the cellular basis of autism and to the development of new therapeutic interventions. We also we have shown that the anatomy of the cerebral cortex is altered by the administration of autism-specific human maternal auto-antibodies during prenatal development. We found that the prenatal exposure to maternal antibodies produces behavioral changes in offspring and increased the size of neurons in the cerebral cortex.


CEREBRAL CORTEX DEVELOPMENT

We contributed to a series of studies identifying a new neural precursor cell type, which we called ‘intermediate progenitor cell’ (IP), and which resides in a proliferative structure termed the subventricular zone. We demonstrated that estrogen regulates IP cell proliferation during neocortical development, and through comparative studies we showed that IP cells in the prenatal brain played a crucial role in the evolution of the human cerebral cortex.


FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME (FXTAS) ANATOMY AND PATHOLOGY

FXTAS is a progressive neurodegenerative disorder that affects carriers of the FMR1 premutation. Our data indicate that FXTAS is associated with white matter disease and not simply a consequence of dysregulation of neural cells in grey matter. Our research on postmortem brains has revealed that many cases of FXTAS present with white matter micro-bleeding, that iron accumulates in very high concentration in the brain capillaries and neural cells, and that white matter microglia are numerous and highly activated. We also demonstrated that, contrary to previously believed, endothelial cells and Purkinje cells contain large intranuclear inclusions.



CEREBRAL CORTEX EVOLUTION

Cortical evolution has long been one of Dr. Martínez Cerdeño’s dearest interests. Our research in cortical evolution has focused on the transition from the three-layered lissencephalic cortex to the six-layered gyrencephalic cortex, from both an evolutionary and a developmental perspective. One of our most notable contributions to this field was the introduction of the “two-step hypothesis of cortical evolution”. This hypothesis posits that the production of excitatory cortical neurons takes place through a two-step process where radial glial cells produce IP cells, which then generate cortical neurons. We have provided evidence that this process evolved very early in the vertebrate brain, perhaps at the divergence of mammals and reptiles. Furthermore, we propose that this mechanism of cell generation is responsible for the expansion of the cerebral cortex that took place in mammalian evolution. Since formulating this hypothesis we have published multiple papers adding novel information that corroborate the role of the two-step process of neurogenesis in the evolution of the mammalian cerebral cortex. In addition to our studies in multiple animal species, we have introduced the bat as a model for cortical evo-devo research. The bat brain presents with unique mechanisms of cortical development, particularly concerning neurogenic period and length of the cell cycle. Our interest in cortical evolution led us to establish and triennially organize the “Cortical Evolution” Conference.



TREATMENTS FOR NEURODEGENERATIVE DISEASES

As a parallel line of research, we have developed a line of novel treatments for neurodegenerative diseases. We have worked on animal models of Parkinson’s disease (PD) and spinal cord injury (SCI). We developed a novel model of SCI based on the use of forceps to produce compression injuries of the spinal cord. The calibrated forceps model of compression injury is a convenient, low cost, and very reproducible animal model that will facilitate SCI research worldwide. One of our most notable treatments is based on the use of stem cells with an inhibitory neuronal fate to treat PD. This approach to treat PD, which differs from traditional approaches that focus on augmenting dopaminergic cells, has opened new avenues of research in the field of neurodegenerative treatment design.



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