Jacob Lab - Labs - University of Pittsburgh School of Medicine Department of Pharmacology & Chemical Biology

How does the neurotransmitter GABA produce myriad forms of inhibition in the central nervous system (CNS), restraining and shaping electrical activity to prevent anxiety, agitation, seizures, chronic pain and sleep disturbance? The majority of fast synaptic inhibition in the CNS is mediated by GABA type A neurotransmitter receptors (GABA_ARs) which are Cl- selective ligand-gated ion channels composed of 5 subunits (from up to 17 different subunits), with differential expression across brain regions, cell types and subcellular localization. The Jacob lab’s broad goal is to understand the impact of dynamically regulated GABA_AR surface levels and distribution in normal development and pathological conditions. The lab uses a combination of molecular, biochemical, cell biological and live-imaging approaches. GABA_AR are the sites of action of many clinically important drugs, including the benzodiazepines (BZ), which are front line treatments for anxiety, insomnia, schizophrenia and epilepsy. The Jacob lab is investigating modulation of GABA_AR trafficking and synaptic inhibition by BZ and other GABAergic agents.

Another area of research in the lab focuses on the role of GABAergic signaling in CNS development and plasticity. The majority of excitatory synapses in the brain are located at the end of dendritic spines, small protrusions from neuronal processes, with neighboring GABAergic synapses predominantly located on dendritic shafts. We have shown that higher GABA_AR surface levels leads to more inhibitory synapses, enhanced inhibitory synaptic transmission and a deficit in mature dendritic spines. Alterations in the excitatory/inhibitory ratio of neuronal signaling, abnormal spine morphology and mutations in GABA_AR subunits are associated with many neurological disorders including autism and other neurodevelopmental disorders. The Jacob lab is investigating the contribution of GABAergic inhibition to dendritic spine morphology, movement and plasticity. These studies aim to improve understanding of how GABAergic dysfunction contributes to human neurodevelopmental disorders including autism.

Joshua Lorenz - Guertin

(MED '19)

Advisor

Tija C. Jacob, PhD

Dissertation

REGULATION OF GABAAR SIGNALING AND NEUROADAPTATIONS IN RESPONSE TO DIAZEPAM. (2019)

Caitlyn Chapman

Journal Articles

Garrudo FFF, Mikael PE, Xia K, Silva JC, Ouyang Y, Chapman CA, Hoffman PR, Yu Y, Han X, Rodrigues CAV, Cabral JMS, Morgado J, Ferreira FC, Linhardt RJ. The effect of electrospun scaffolds on the glycosaminoglycan profile of differentiating neural stem cells. Biochimie. 2021 Mar;182:61-72. doi: 10.1016/j.biochi.2021.01.001. Epub: 2021 Jan 7.

Garrudo FFF, Mikael PE, Rodrigues CAV, Udangawa RW, Paradiso P, Chapman CA, Hoffman P, Colaço R, Cabral JMS, Morgado J, Linhardt RJ, Ferreira FC. Polyaniline-polycaprolactone fibers for neural applications: Electroconductivity enhanced by pseudo-doping. Mater Sci Eng C Mater Biol Appl. 2021 Jan;120:111680. doi: 10.1016/j.msec.2020.111680. Epub: 2020 Nov 4

Bhattacharya S, Roy I, Tice A, Chapman C, Udangawa R, Chakrapani V, Plawsky JL, Linhardt RJ. High-Conductivity and High-Capacitance Electrospun Fibers for Supercapacitor Applications. ACS Appl Mater Interfaces. 2020 Apr 29;12(17):19369-19376. doi: 10.1021/acsami.9b21696. Epub: 2020 Apr 20.

Garrudo, F.F.F.; Udangawa, R.N.; Hoffman, P.R.; Sordini, L.; Chapman, C.A.; Mikael, P.E.; Ferreira, F.A.; Silva, J.C.; Rodrigues, C.A.V.; Cabral, J.M.S.; Morgado, J.M.F.; Ferreira, F.C.; Linhardt, R.J.Polybenzimidazole nanofibers for neural stem cell culture. Materials Today Chemistry. December 2019;14. doi: 10.1016/j.mtchem.2019.08.004.

Tija C. Jacob, PhD

Journal Articles

Nuwer JL, ML Brady, NV Povysheva, A Coyne and TC Jacob. Sustained treatment with an α5 GABA A receptor negative allosteric modulator delays excitatory circuit development while maintaining GABAergic neurotransmission. Neuropharmacology 197:108724, 2021.

Lombardi JP, DA Kinzlmaier and TC Jacob. Visualizing GABA A receptor trafficking dynamics with fluorogenic protein labeling. Curr Protoc Neurosci 92:e97, 2020

Jacob TC. Neurobiology and therapeutic potential of α5-GABA Type A receptors. Front Mol Neurosci. 2019;12:179. doi: 10.3389/fnmol.2019.00179. eCollection 2019.

Ye J, S Das, A Roy, W Wei, H Huang, JM Lorenz-Guertin, Q Xu, TC Jacob, B Wang, D Sun and QJ Wang. Ischemic injury-induced CaMKIIδ and CaMKIIγ confer neuroprotection through the NF-κB signaling pathway. Mol Neurobiol 56(3):2123-2136, 2019.

Lorenz-Guertin JM, MJ Bambino, S Das, ST Weintraub and TC Jacob. Diazepam accelerates GABAAR synaptic exchange and alters intracellular trafficking. Front Cell Neurosci. 2019;13:163. doi: 10.3389/fncel.2019.00163. eCollection 2019.

Drombosky KW, S Rode, R Kodali, TC Jacob, MJ Palladino and R Wetzel. Mutational analysis implicates the amyloid fibril as the toxic entity in Huntington's disease. Neurobiol Dis 120:126-138, 2018.,

Brady ML, J Pilli, JM Lorenz-Guertin, S Das, CE Moon, N Graff and TC Jacob. Depolarizing, inhibitory GABA type A receptor activity regulates GABAergic synapse plasticity via ERK and BDNF signaling. Neuropharmacology 128:324-339, 2018.

Lorenz-Guertin JM, MJ Bambino and TC Jacob. γ2 GABAAR trafficking and the consequences of human genetic variation front. Cell Neurosci 12:265, 2018.

Lorenz-Guertin JM and TC Jacob. GABA type a receptor trafficking and the architecture of synaptic inhibition. Dev Neurobiol 78(3):238-270, 2018.

Lorenz-Guertin JM, MR Wilcox, M Zhang, MB Larsen, J Pilli, BF Schmidt, MP Bruchez, KW Johnson, AS Waggoner, SC Watkins and TC Jacob. A versatile optical tool for studying synaptic GABAA receptor trafficking. J Cell Sci 130(22):3933-3945, 2017.

Brady ML and TC Jacob. Synaptic localization of α5 GABA (A) receptors via gephyrin interaction regulates dendritic outgrowth and spine maturation. Dev Neurobiol 75(11):1241-1251, 2015.

Petrini EM, T Ravasenga, TJ Hausrat, G Iurilli, U Olcese, V Racine, JC Sibarita, TC Jacob et al. Synaptic recruitment of gephyrin regulates surface GABBA receptor dynamics for the expression of LTP. Nat Commun 5:3921, 2014