Profiles

Rocco Gogliotti, PhD

Research Interests

Ongoing Research

Among the biggest challenges facing neuroscience drug discovery is the failure of promising preclinical data sets to translate into clinical efficacy. One potential contributing factor is an overreliance on mouse models during target identification, particularly knockout mice, which do not often represent the subtleties of clinically pathogenic mutations. The Gogliotti lab uses a multifaceted strategy that integrates pharmacology, genomics, and neuroscience, and emphasizes the use of human autopsy samples early in the discovery process with the goal of enriching drug targets for autism and autism-associated disorders with those that are translationally relevant. The main projects within the lab fall under three categories:

Precision Medicine

Using a large set of autopsy samples from patients diagnosed with the neurodevelopmental disorder Rett syndrome (RTT), we have discovered that distinct pathogenic mutations have unique effects on gene expression patterns. RTT is caused by loss of function mutations in the methyl CpG binding protein 2 (MeCP2) gene, and our findings complement clinical data demonstrating that the type and location of MeCP2 mutation is predictive of disease severity. Since target identification for RTT is almost exclusively driven by data from Mecp2 knockout mice, these data indicate that patient subpopulations could have unique responses to compounds currently being advanced for clinical use. Our goal is to 1) determine how common mutations impact the safety and efficacy profiles of these compounds across the spectrum of MeCP2 mutations and 2) examine how mutation-specific patterns of gene expression alter disease severity.

Muscarinic Acetylcholine Receptors (mAChRs) as Targets for Neurodevelopmental Diseases

In Gogliotti et al. 2018, we conducted an RNA-sequencing experiment on motor cortex and cerebellar samples from RTT patient autopsies, which uncovered that four of the five mAChRs had significantly affected gene expression relative to matched controls. mAChRs are widely considered to be valuable drug targets based on their signaling properties and location within the brain; however, mAChR drug discovery has been plagued by adverse effects, and only recently have clinically viable compounds become available. Using these compounds, which target mAChR receptors allosterically, we have now demonstrated efficacy in mouse models of RTT, CDKL5-disorder, and Pitt Hopkins Syndrome. We are currently examining how the loss of mAChR signaling impacts neurodevelopment and the mechanisms underlying the observed efficacy.

Convergent Signaling Amongst Common and Rare Variants

95% of RTT cases result from mutations in MeCP2; however, despite sharing sufficient symptomatic overlap to support a RTT diagnosis, the remaining 5% are MeCP2 mutation-negative. Working under the hypothesis that the pathways whose disruption is conserved between both populations will likely be the most critical to disease manifestation, we recently performed differential sequencing analysis of the transcriptomes in temporal cortex samples from mutation-positive and negative patients.  These experiments suggest that pathways associated with activity-dependent gene regulation may be implicated in the disorder. We are currently exploring this using a combination of neurobehavioral assays, transcriptomics, and pharmacology.

Selected Publications

• M. Smith, B. Arthur, J. Cikowski, C. Holt, S. Gonzalez, N.M. Fisher, S.A.D. Vermudez, C.W. Lindsley, C.M. Niswender and R.G. Gogliotti. Clinical and preclinical evidence for M₁ Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome. Neurotherapeutics https://link.springer.com/article/10.1007/s13311-022-01254-3
• Jakub Cikowski*, Calista Holt*, Bright Arthur, Mackenzie Smith, Sonia Gonzalez, Craig W. Lindsley, Colleen M. Niswender, and R.G. Gogliotti Optimized Administration of the M₄ PAM VU0467154 Demonstrates Broad efficacy, but Limited Effective Concentrations in Mecp2⁺/- mice ACS Publications https://pubs.acs.org/doi/10.1021/acschemneuro.2c00113
• Gogliotti, R. G., and Niswender, C. M. (2019) A Coordinated Attack: Rett Syndrome Therapeutic Development Trends in pharmacological sciences 40, 233-236
• Joffe, M. E., Santiago, C. I., Stansley, B. J., Maksymetz, J., Gogliotti, R. G., Engers, J. L., Nicoletti, F., Lindsley, C. W., and Conn, P. J. (2019) Mechanisms underlying prelimbic prefrontal cortex mGlu3/mGlu5-dependent plasticity and reversal learning deficits following acute stress Neuropharmacology 144, 19-28
• Gogliotti, R. G., Fisher, N. M., Stansley, B. J., Jones, C. K., Lindsley, C. W., Conn, P. J., and Niswender, C. M. (2018) Total RNA Sequencing of Rett Syndrome Autopsy Samples Identifies the M4 Muscarinic Receptor as a Novel Therapeutic Target The Journal of pharmacology and experimental therapeutics 365, 291-300
• Stansley, B. J., Fisher, N. M., Gogliotti, R. G., Lindsley, C. W., Conn, P. J., and Niswender, C. M. (2017) Contextual Fear Extinction Induces Hippocampal Metaplasticity Mediated by Metabotropic Glutamate Receptor 5 Cerebral cortex, 1-14
• Fisher, N. M.*, Gogliotti, R. G.*, Vermudez, S. A. D., Stansley, B. J., Conn, P. J., and Niswender, C. M. (2017) Genetic Reduction or Negative Modulation of mGlu7 Does Not Impact Anxiety and Fear Learning Phenotypes in a Mouse Model of MECP2 Duplication Syndrome ACS chemical neuroscience
• Abe, M*., Seto, M.*, Gogliotti, R. G.*, Loch, M. T., Bollinger, K. A., Chang, S., Engelberg, E. M., Luscombe, V. B., Harp, J. M., Bubser, M., Engers, D. W., Jones, C. K., Rodriguez, A. L., Blobaum, A. L., Conn, P. J., Niswender, C. M., and Lindsley, C. W. (2017) Discovery of VU6005649, a CNS Penetrant mGlu7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines ACS medicinal chemistry letters 8, 1110-1115
• Gogliotti, R. G., Senter, R. K., Fisher, N. M., Adams, J., Zamorano, R., Walker, A. G., Blobaum, A. L., Engers, D. W., Hopkins, C. R., Daniels, J. S., Jones, C. K., Lindsley, C. W., Xiang, Z., Conn, P. J., and Niswender, C. M. (2017) mGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome Science translational medicine 9
• Ponnazhagan, R., Harms, A. S., Thome, A. D., Jurkuvenaite, A., Gogliotti, R., Niswender, C. M., Conn, P. J., and Standaert, D. G. (2016) The Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator ADX88178 Inhibits Inflammatory Responses in Primary Microglia Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 11, 231-237
• Gogliotti, R. G., Senter, R. K., Rook, J. M., Ghoshal, A., Zamorano, R., Malosh, C., Stauffer, S. R., Bridges, T. M., Bartolome, J. M., Daniels, J. S., Jones, C. K., Lindsley, C. W., Conn, P. J., and Niswender, C. M. (2016) mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome Human molecular genetics 25, 1990-2004
• Gogliotti, R. G., and Conn, P. J. (2016) Pharmacological Treatments for Autism Spectrum Disorder: Will Emerging Approaches Yield New Treatments? Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 41, 376-377
• Gogliotti, R. G., Cardona, H., Singh, J., Bail, S., Emery, C., Kuntz, N., Jorgensen, M., Durens, M., Xia, B., Barlow, C., Heier, C. R., Plasterer, H. L., Jacques, V., Kiledjian, M., Jarecki, J., Rusche, J., and DiDonato, C. J. (2013) The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models Human molecular genetics 22, 4084-4101
• Gogliotti, R. G., Quinlan, K. A., Barlow, C. B., Heier, C. R., Heckman, C. J., and Didonato, C. J. (2012) Motor neuron rescue in spinal muscular atrophy mice demonstrates that sensory-motor defects are a consequence, not a cause, of motor neuron dysfunction The Journal of neuroscience : the official journal of the Society for Neuroscience 32, 3818-3829
• Gogliotti, R. G., Lutz, C., Jorgensen, M., Huebsch, K., Koh, S., and Didonato, C. J. (2011) Characterization of a commonly used mouse model of SMA reveals increased seizure susceptibility and heightened fear response in FVB/N mice Neurobiology of disease 43, 142-151
• Kular, R. K., Gogliotti, R. G., and Opal, P. (2010) Cpd-1 null mice display a subtle neurological phenotype PloS one 5
• Hammond, S. M., Gogliotti, R. G., Rao, V., Beauvais, A., Kothary, R., and DiDonato, C. J. (2010) Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late PloS one 5, e15887
• Gogliotti, R. G., Hammond, S. M., Lutz, C., and Didonato, C. J. (2010) Molecular and phenotypic reassessment of an infrequently used mouse model for spinal muscular atrophy Biochemical and biophysical research communications 391, 517-522
• Gavrilina, T. O., McGovern, V. L., Workman, E., Crawford, T. O., Gogliotti, R. G., DiDonato, C. J., Monani, U. R., Morris, G. E., and Burghes, A. H. (2008) Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect Human molecular genetics 17, 1063-1075
• Heier, C. R., Gogliotti, R. G., and DiDonato, C. J. (2007) SMN transcript stability: could modulation of messenger RNA degradation provide a novel therapy for spinal muscular atrophy? Journal of child neurology 22, 1013-1018
• Wang, X., Gargalovic, P., Wong, J., Gu, J. L., Wu, X., Qi, H., Wen, P., Xi, L., Tan, B., Gogliotti, R., Castellani, L. W., Chatterjee, A., and Lusis, A. J. (2004) Hyplip2, a new gene for combined hyperlipidemia and increased atherosclerosis Arteriosclerosis, thrombosis, and vascular biology 24, 1928-1934