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Tija C. Jacob, PhD

Associate Professor & Vice Chair for Graduate Education
W1351 Thomas E. Starzl Biomedical Science Tower
200 Lothrop St.
Pittsburgh, PA 15213
tcj11@pitt.edu
Phone: 412-648-8136
Fax: 412-648-1945

Education

BA (Zoology), University of Texas at Austin, 1996
PhD (Molecular and Cell Biology), University of California, Berkeley, 2002

Links

Headshot of Tija C. Jacob, PhD

Labs

GABA ReceptorHow 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 (GABAARs) 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 GABAAR surface levels and distribution in normal development and pathological conditions. The lab uses a combination of molecular, biochemical, cell biological and live-imaging approaches. GABAAR 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 GABAAR trafficking and synaptic inhibition by BZ and other GABAergic agents. 

 

 

Synapse Model

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 GABAAR 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 GABAAR 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.

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

Sponsored Research

Benzodiazepine treatment induced neuroplasticity - 2/1/2019 - 11/30/2022
NIH - R01MH114908-01
Benzodiazepine treatment induced neuroplasticity - 1/1/2018 - 12/31/2019
NIH - R56MH114908