Cerebellar Neurobiology in Health and Disease

Research at the Cerebellar Neurobiology in Health and Disease Lab focuses on understanding the role of the cerebellum under both physiological and pathological conditions. While traditionally considered as a brain region primarily involved in motor coordination, the cerebellum is now increasingly recognized for its role in emotional regulation, cognitive processing, and social behaviour. Cerebellar dysfunction has been implicated in a range of neuropsychiatric and neurodevelopmental disorders, including primary mitochondrial diseases, Rett syndrome, schizophrenia, and bipolar disorder. Our research aims to elucidate the cellular and subcellular mechanisms underlying cerebellar function and dysfunction, with the ultimate goal of understanding how cerebellar abnormalities contribute to brain disorders. The lab is embedded in a network of collaborators that includes Dr. Valjent (CNRS, France), Dr. Quintana (UAB), and Dr. Márquez Ruiz (UPO), providing a multidisciplinary framework to address the complexity of cerebellar function in health and disease.

• Deciphering cell type-specific molecular mechanisms underlying cerebellar dysfunction in Rett Syndrome.
• Characterizing the expression and function of metabotropic GABA-B receptors in Purkinje cell mitochondria.
• Investigating the role of Aquaporin-4 in the pathophysiology of Rett Syndrome and its regulation by noradrenergic signaling.
• Elucidating cholinergic signaling pathways in the cerebellum.

Our research is dedicated to understanding cerebellar dysfunction in Rett Syndrome by elucidating cell type-specific molecular mechanisms and mitochondrial abnormalities. We focus on uncovering molecular alterations in a specific subtype of cerebellar GABAergic neurons: the parvalbumin-expressing (PV) neurons. These neurons are characterized by fast-spiking activity and high metabolic demand, rendering them particularly vulnerable in this disorder. To investigate these changes, we utilize the Pvalb-Cre;Mecp2;Ribotag mouse model for transcriptional profiling of cerebellar PV neurons, allowing us to gain detailed molecular insights into the disrupted cerebellar pathways in Rett Syndrome.

Previous studies performed in our group indicated that GABAergic signaling is impaired in the caudal cerebellum of Rett Syndrome mice, notably through reduced expression of the metabotropic GABA_B receptor subunits 1 and 2. A central aim of our work is to characterize the subcellular localization of these receptors, with particular emphasis on their mitochondrial presence. To achieve this, we employ advanced techniques including high-resolution confocal microscopy, electron microscopy, proteomics, and the MitoTag approach.