Tija C. Jacob, PhD

  • Assistant Professor, Pharmacology & Chemical Biology
  • Vice Chair for Graduate Education

Phone

412-648-8136

E-mail

tcj11@pitt.edu

Personal Website

website link

Education & Training

PhD, University of California, Berkeley (2002)

Location

W1351 Starzl Biomedical Science Tower

Research Interest Summary

Regulation of GABAergic inhibition in development and mental disorders

Research Summary

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?

How does GABAergic dysfunction impair early brain circuit development and contribute to neurodevelopmental disorders?

The majority of fast synaptic inhibition in the CNS is mediated by GABA type A neurotransmitter receptors (GABAARs) which are chloride (Cl-) selective ligand-gated ion channels composed of five subunits (from up to 19 unique subunits in humans), with differential expression across brain regions, cell types and subcellular localization. The Jacob lab’s broad goal is to identify molecular mechanisms regulating dynamic GABAAR inhibition and understand how this impacts neurodevelopment and synaptic plasticity and is modified by drug treatment and pathological conditions. We use a combination of biochemical, pharmacological, functional and imaging based approaches.

 

Main Projects

Benzodiazepine induced neuroplasticity

GABAAR are the sites of action of many clinically important drugs, including the benzodiazepines (BZs), which are front line treatments for anxiety, insomnia, schizophrenia and epilepsy. Although effective, BZ use is limited by the development of tolerance, dependence, and withdrawal. The Jacob lab is investigating modulation of GABAAR trafficking and inhibition by BZs and other GABAAR targeted drugs.  More broadly, we are applying biochemical, proteomic, novel optical methods and electrophysiological approaches to identify neuroadaptations induced by BZ treatment both at excitatory and inhibitory synapses.

Significance:  Knowledge generated by these studies will advance therapies to treat BZ tolerance.

 GABA A receptor subtype regulation of brain circuit formation

Many neurodevelopmental disorders including autism, intellectual disability, and childhood epilepsy syndromes share a common cause – dysfunction in GABAergic neurotransmission. Mutations in GABAAR subunits and other imbalances in the ratio of excitatory/inhibitory neuronal signaling produce these pathologies. 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 but also found on dendritic spines. Importantly, GABAAR subunit composition largely defines receptor localization, interacting proteins, electrophysiological properties and drug sensitivities. The Jacob lab is investigating GABAAR subtype specific mechanisms regulating early neuronal development and circuit formation.  

Significance: This research will improve understanding of how GABAergic dysfunction contributes to neurodevelopmental disorders.

Jacob TCNeurobiology and Therapeutic Potential of α5-GABA Type A Receptors. Front Mol Neurosci. 2019;12:179. doi: 10.3389/fnmol.2019.00179. eCollection 2019. PubMed PMID: 31396049; PubMed Central PMCID: PMC6668551.

Lorenz-Guertin JM, Bambino MJ, Das S, Weintraub ST, Jacob TCDiazepam Accelerates GABAAR Synaptic Exchange and Alters Intracellular Trafficking. Front Cell Neurosci. 2019;13:163. doi: 10.3389/fncel.2019.00163. eCollection 2019. PubMed PMID: 31080408; PubMed Central PMCID: PMC6497791.

Ye J, Das S, Roy A, Wei W, Huang H, Lorenz-Guertin JM, Xu Q, Jacob TC, Wang B, Sun D, Wang QJ. Ischemic Injury-Induced CaMKIIδ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway. Mol Neurobiol. 2019 Mar;56(3):2123-2136. doi: 10.1007/s12035-018-1198-2. Epub 2018 Jul 11. PubMed PMID: 29992531; PubMed Central PMCID: PMC6394630.

Drombosky KW, Rode S, Kodali R, Jacob TC, Palladino MJ, Wetzel R. Mutational analysis implicates the amyloid fibril as the toxic entity in Huntington's disease. Neurobiol Dis. 2018 Dec;120:126-138. doi: 10.1016/j.nbd.2018.08.019. Epub 2018 Aug 30. PubMed PMID: 30171891; PubMed Central PMCID: PMC6186178.

Lorenz-Guertin JM, Bambino MJ, Jacob TCγ2 GABAAR Trafficking and the Consequences of Human Genetic Variation.Front Cell Neurosci. 2018;12:265. doi: 10.3389/fncel.2018.00265. eCollection 2018. Review. PubMed PMID: 30190672; PubMed Central PMCID: PMC6116786.

Lorenz-Guertin JM, Jacob TCGABA type a receptor trafficking and the architecture of synaptic inhibition. Dev Neurobiol.2018 Mar;78(3):238-270. doi: 10.1002/dneu.22536. Epub 2017 Sep 19. Review. PubMed PMID: 28901728; PubMed Central PMCID: PMC6589839.

Brady ML, Pilli J, Lorenz-Guertin JM, Das S, Moon CE, Graff N, Jacob TCDepolarizing, inhibitory GABA type A receptor activity regulates GABAergic synapse plasticity via ERK and BDNF signaling. Neuropharmacology. 2018 Jan;128:324-339. doi: 10.1016/j.neuropharm.2017.10.022. Epub 2017 Oct 23. PubMed PMID: 29074304; PubMed Central PMCID: PMC5739058.

Lorenz-Guertin JM, Wilcox MR, Zhang M, Larsen MB, Pilli J, Schmidt BF, Bruchez MP, Johnson JW, Waggoner AS, Watkins SC, Jacob TCA versatile optical tool for studying synaptic GABAA receptor trafficking. J Cell Sci. 2017 Nov 15;130(22):3933-3945. doi: 10.1242/jcs.205286. Epub 2017 Oct 12. PubMed PMID: 29025969; PubMed Central PMCID: PMC5702044.

Brady ML, Jacob TCSynaptic localization of α5 GABA (A) receptors via gephyrin interaction regulates dendritic outgrowth and spine maturation. Dev Neurobiol. 2015 Nov;75(11):1241-51. doi: 10.1002/dneu.22280. Epub 2015 Feb 18. PubMed PMID: 25663431; PubMed Central PMCID: PMC5240477.

Petrini EM, Ravasenga T, Hausrat TJ, Iurilli G, Olcese U, Racine V, Sibarita JB, Jacob TC, Moss SJ, Benfenati F, Medini P, Kneussel M, Barberis A. Synaptic recruitment of gephyrin regulates surface GABAA receptor dynamics for the expression of inhibitory LTP. Nat Commun. 2014 Jun 4;5:3921. doi: 10.1038/ncomms4921. PubMed PMID: 24894704; PubMed Central PMCID: PMC4059940.

Brady ML, Moon CE, Jacob TCUsing an α-bungarotoxin binding site tag to study GABA A receptor membrane localization and trafficking. J Vis Exp. 2014 Mar 28;(85). doi: 10.3791/51365. PubMed PMID: 24747556; PubMed Central PMCID: PMC4159110.