Grupo CerebralCortex – Structural and functional alterations of neuronal circuits in the cingulate area of the cerebral cortex caused by dysfunction of genes involved in brain diseases

STRUCTURAL AND FUNCTIONAL ALTERATIONS OF NEURONAL CIRCUITS IN THE CINGULATE AREA OF THE CEREBRAL CORTEX CAUSED BY DYSFUNCTION OF GENES INVOLVED IN BRAIN DISEASES

There are many genes involves in the origin of brain diseases. LIS1 is one of the principal genes related to Type I lissencephaly, a severe human brain malformation characterized by a smooth brain and deep cortical alterations. The protein Lis1 is implicated in neuronal growth and migration and it is necessary for the development of the cerebral cortex. There are evidences that LIS1 mutations are related with other brain diseases (such as schizophrenia and bipolar disorder) whose cause is also related to an altered cortical development. The gene DISC1 is related to the development of schizophrenia, and the products of these two genes (LIS1 and DISC1) are closely related in intracellular signaling pathways. Therefore, the study of the consequences of LIS1 and DISC1 mutation may reveal common pathophysiological mechanisms involved in these diseases related to alterations of the brain development.

Our goal is to analyze the consequences (developmental, structural and functional) of the mutation of the LIS1 and DISC1 genes on the cortical system formed by the anterior cingulate cortex (ACC) and the retrosplenial cortex (RSC) in the mouse. The objectives of the project are the study of the abnormalities on: a) the prenatal developmental of the interconnections formed between ACC and RSC and the structure and distribution of different types of cortical neurons (pyramidal and inhibitory interneurons); b) the electrophysiology of the neuronal circuits formed between ACC and RSC in the postnatal brain, and the propagation of epileptiform activity as a way to evaluate the working of the neuronal cortical circuits of these cortical regions; c) the cortical functional properties studied by recording electrophysiological activity and calcium imaging in intact animals; and d) the animal behavior studied using specific tests to explore the functions of ACC or RSC. The experiments will be done in several types of LIS1 and DISC1 mutant mice, including specific mouse lines that will allow us to introduce inactivating mutations of these genes into specific cortical neuronal types (cortical pyramidal neurons and interneurons); we will also use the Lis1/sLis1 model, which is a model of lissencepahly in which the LIS1 mutation is expressed in all neurons. We expect to obtain relevant results on the structural and functional abnormalities caused by LIS1 and DISC1 mutation that may shed new light on the pathophysiological mechanisms underlying some brain diseases.

PROMETEO PUBLICATIONS

1. José Manuel Hernandez Lopez, Cristina Hernandez Medina, Cristina Medina Corvalan, Mónica Rodenas, Almagro Francisca, Claudia Perez Garcia, Diego Echevarria, Francisco Carratala, Emilio Geijo Barrientos, Salvador Martínez. (2023). Neuronal progenitors of the dentate gyrus express the SARS CoV 2 cell receptor during migration in the developing human hippocampus. Cellular and Molecular Life Sciences. May 7;80(6):140 https://doi.org/10.1007/s00018-023-04787-8. PMID: 37149825. F.I.: 8

2. Martínez-Morga, Marta; Hernandez-Lopez, Jose Manuel; Hernandez-Medina, Cristina; Martínez-Morga, Salvador; Martínez, Salvador (2023). ACE2 expression in the brain during development and susceptibility to brain infection by SARS-COV-2 [Expresión de Ace2 en Cerebro Durante el Desarrollo y Susceptibilidad de Infección Cerebral por SARS-COV-2]. Medicina (Argentina)Volume 83, Pages -2-5. PMID: 36820474.

3. Jesús A. Pérez-Cabello, Lucía Silvera-Carrasco, Jaime M. Franco, Vivian Capilla-Gonzalez, Alexandros Armaos, María Gómez-Lima, Raquel García-García, Xin Wen Yap, Magdalena M. Leal-Lasarte, Deepti Lall Robert H. Baloh, Salvador Martinez, Yoshihiko Miyata, Gian Gaetano Tartaglia, Ritwick Sawarkar, Mario Garcia-Dominguez, David Pozo, Cintia Roodveldt. (2023). MAPK/MAK/MRK overlapping kinase (MOK) controls microglial inflammatory/type-I IFN responses via Brd4 and is involved in ALS. PNAS. PMID: 37399380.DOI https://doi.org/10.1073/pnas.2302143120. F.I.: 11,1

4. Ana Pombero, Raquel Garcia-Lopez and Salvador Martínez. (2023). Pericyte-Glioblastoma Cell Interaction: A Key Target to Prevent Glioblastoma Progression. Cells. Mayo 2023. https://doi.org/10.3390/cells12091324. PMID 37174724. F.I. : 6