Welcome to the Laboratory of Molecular Neurobiology at the Boston University School of Medicine. The members of the laboratory are working together as a team under the direction of David H. Farb, PhD, to elucidate the mechanisms by which receptors are regulated, how activation of these receptors modulates neural network activity in vivo and, how this in turn contributes to the onset and progression of memory deficits in age-related neurodegenerative diseases. The laboratory uses a systems neuroscience approach to understanding the functional interactions within neural networks implicated in neurological and psychiatric diseases. Dr. David Farb and the other members of the Laboratory of Molecular Neurobiology are among the first to use in vivo electrophysiological techniques to advanced our understanding of how drugs modulate neural network activities implicated in memory deficits associated with age-related amnestic mild cognitive impairment (Hippocampus, 2015). The Laboratory is currently using this same technology combined with ultra fine silicon microelectrode arrays (see figures and video below) to identify changes in local field potentials and single unit activity that underlie cognitive deficits associated with aging and disease and, to assess for the functional neural network correlates associated with effective therapeutics for Alzheimer’s disease. Due to their unique design and flexible layouts, silicon probe microelectrode arrays permit for recording across strata within a subregion as well as from one or more subregions. The figures below demonstrate how local field potential data is acquired and visualized for analysis of single unit activity associated with sharp wave ripples events in the CA1 hippocampal subregion (sharp wave ripple event is shown inside box in lower figure). This research is funded in part by the National Institute on Aging. The Laboratory of Molecular Neurobiology is part of the Boston University Center for Systems Neuroscience.
Sharp Wave Ripple with Associated Single Unit Activity
Silicon Probe Array Video
Hippocampal Place Cells
In vivo electrophysiological recordings have been used to study neuronal activity and hippocampal dependent learning and memory function since the Nobel Prize winning discovery of “Place Cells” by O’Keefe and Dostrovsky in 1971. Place cells, are hippocampal pyramidal cells that fire with a greater frequency when an animal is in a specific location. This activity pattern can be visualized in the video below of the Dancing Place Cells which was made from actual data recordings of hippocampal place cells.
The Dancing Place Cells
These cells establish stable place fields within a given environment and change their firing patterns (“remap”) when the animal is moved to a novel location in a classic remapping paradigm such as that shown in the video below.
Remapping Paradigm Video
The figure below shows the place fields of a rat “remapping” when the animal is moved from a familiar square environment to a novel cylindrical one. The activity of these place cells is altered by aging and disease. Place cell activity can also be modulated with drugs (a.k.a., cognitive enhancers). In recent years, advances in vivo electrophysiology coupled with increased understanding of place cell firing dynamics has opened the door to the use of this technology as a research tool in the preclinical drug discovery process. Pyramidal cells with defined place fields in at least one environment are subsequently analyzed for drug-induced effects on firing rates, spatial correlations across environments, and spatial information content per spike.
Analysis of In vivo Electrophysiological Data
Post-hoc differentiation of pyramidal “complex spike” cells (see top image below) and interneurons (see bottom image below) is facilitated in part by evaluation of auto-correlograms (far left panel), which show distinct patterns of activity, with pyramidal cells showing “complex spikes” characterized by bursts of action potentials immediately following the refractory period. Pyramidal cells are further differentiated from interneurons by the mean firing rates of the cell and the trough to peak width of their waveforms. Note that the pyramidal cells also have distinct place fields (far right panel) while the interneurons do not.
Custom Nichrome Tetrode Arrays
The Laboratory of Molecular Neurobiology also acquires in vivo electrophysiological data with custom made nichrome microtetrode arrays (such as the one pictured below). The video below shows how these arrays are constructed. These arrays allow us to simultaneously record drug-induced changes in the activity of single place cells and local field potentials from one or more hippocampal subregions (e.g., CA3 and CA1 ) in freely behaving rodents.The microelectrode arrays contain tetrodes, comprised of four nichrome micro-electrodes, such as the one pictured below (top) which can be lowered into the hippocampal subregion of interest by turning the screw on a microdrive (bottom).
Microelectrode Array Construction Video
These tetrodes allow for isolation of individual pyramidal cells based on the proximity of the cell to each of the four wires of the tetrode. The action potentials or “spikes” of individual neurons such as those pictured below are “sorted” manually using Plexon Offline Sorter software as shown below or via semi-automated sorting program for subsequent analysis. Well-isolated cells such as the one pictured below in yellow show amplitude differences reflecting their proximity to the four poles of the tetrode.
Observations and Results
We have effectively used the methods described above to demonstrate that co-administration of sub-therapeutic doses of the FDA approved anti-epileptic agents levetiracetam and valproic acid reduces hippocampal hyperactivity and increases spatial information content (SIC) per action potential (spike) in the CA3 and CA1 hippocampal subregions of aged rats (see histogram of these data below) (Hippocampus, 2015).
Pharmacological modulation of hippocampal circuitry implicated in learning and memory: Connectome shows interactions between inhibitory and excitatory inputs. Putative targets for treating age related learning and memory impairments include enhancement of GABA inhibitory tone and attenuation of glutamate mediated excitation. A loss of inhibitory interneurons in the hilar region has been implicated in CA3 pyramidal cell hyperactivity. Acute administration of LEV + VPA may attenuate the hyperactivity in this region of the hippocampus in part by enhancing GABAergic neurotransmission. Muscarinic and nicotinic acetylcholine receptors provide for suppression of feedback excitation and enhancement of afferent input respectively. Ach = acetylcholine; DA = dopamine; DG = dentate gyrus; ECI = entorhinal cortex layer I; ECII = entorhinal cortex layer II; ECIII = entorhinal cortex layer III; GABA = Gamma Amino Butyric Acid; Glu = glutamate; Loc. Cer. = Locus Coeruleus; Med. Sep. = Medial Septum; NE = norepinephrine; Raphe = raphe nucleus; Sub = subiculum; VTA = Ventral Tegmental Area (Hippocampus, 2015).
Current Laboratory Members
Senior Laboratory Members
Marcia H. Ratner, PhD, DABT, Project Manager
Vidhya Kumaresan, PhD, Research Assistant Professor
Scott S. Downing, PhD, Bioinformatics Specialist
Shelley J. Russek, MA, PhD, Professor or Pharmacology
Weiming Xia, PhD, Professor of Pharmacology
Select Publications and Abstracts
Ratner MH, Kumaresan V, Farb DH: Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders. Frontiers in Endocrinology 2019.[Article]
Robitsek RJ, Ratner MH, Stewart TM, Eichenbaum HB, Farb DH: Combined Administration of Levetiracetam and Valproic Acid Attenuates Age Related Hyperactivity of CA3 Place Cells, Reduces Place Field Area, and Increases Spatial Information Content in Aged Rat Hippocampus. Hippocampus. Hippocampus. 2015 Dec;25(12):1541-55. [Article]
Farb DH, Ratner MH. Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders. Pharmacological Reviews 2014 October: 66:1002-1032. [Article]
Smith C, Martin SC, Sugunan K, Russek SJ, Gibbs TT, Farb DH. A Role for Picomolar Concentrations of Pregnenolone Sulfate in Synaptic Activity-dependent Ca2+ signaling and CREB activation. Molecular Pharmacology 2014 July 23. [Article]
Smith CC, Gibbs TT, Farb DH. Pregnenolone sulfate as a modulator of synaptic plasticity. Psychopharmacology 2014 July 6. [Abstract]
Gutiérrez ML, Ferreri MC, Farb DH, Gravielle MC. GABA-induced uncoupling of GABA/benzodiazepine site interactions is associated with increased phosphorylation of the GABAA receptor. Journal of Neuroscience Research 2014 August; 92(8): 1054-61. [Abstract]
Farb DH (2013). An interview with David H Farb, Section Editor for Basic Pharmacology. BMC Pharmacology and Toxicology 2013 August; 14(42). [Abstract]
Saha S, Hu, Martin SC, Bandyopadhyay S, Russek SJ, Farb DH (2013). Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity. BMC Pharmacology and Toxicology 2013 August; 14(37). [Abstract]
Kostakis E, Smith C, Jang M-K, Martin SC, Richards KG, Russek SJ, Gibbs TT, Farb DH (2013). The Neuroactive Steroid Pregnenolone Sulfate Stimulates Trafficking of Functional NMDA Receptors to the Cell Surface via a Non-Canonical G-Protein and Ca++ Dependent Mechanism. Molecular Pharmacology 2013 May; 83(6). [Abstract]
Kim JH, Roberts DS, Hu Y, Lau GC, Brooks-Kayal AR, Farb DH, Russek SJ (2011) Brain-derived Neurotrophic Factor Uses CREB and Egr3 to Regulate NMDA Receptor Levels in Cortical Neurons. J Neurochem 2012 Jan; 120(2):210-9. [Abstract]
Kostakis E, Jang M-K, Russek SJ, Gibbs TT, Farb DH (2011) A steroid modulatory domain in NR2A collaborates with NR1 exon-5 to control NMDAR modulation by pregnenolone sulfate and protons. J Neurochem 2011 Nov; 119(3): 486-96. [Abstract]
Desbiens S, Farb DH (2011) Medicine and Pathology – Current Needs for New Therapeutic Agents and Discovery Strategies – A Systems Pharmacology Approach. In: Development of Therapeutic Agents (Shayne Gad, Ed.) John Wiley & Sons. [Abstract]
Desbiens S, Farb DH (2010) Current Needs for New Therapeutic Agents and Discovery Strategies – A Systems Pharmacology Approach. In Pharmaceutical Sciences Encyclopedia: Drug Discovery, Development, and Manufacturing (Shayne Gad, Ed.) John Wiley & Sons. [Abstract]
Eagleson KL, Gravielle MC, Schlueter McFadyen-Ketchumm LJ, Russek SJ, Farb DH, Levitt P (2010) Genetic disruption of the autism spectrum disorder risk gene PLAUR induces GABAA receptor subunit changes. Neuroscience 2010 Jul 14; 168(3):797-810. PMC 2880553. [Article]
Kim JH, Farb DH, Russek SJ (2009) Promoter. Encyclopedia of Neuroscience. U. Windhorst, M.D. Binder, N. Hirokawa, and M.C. Hirsch, Editors. Springer Publishing, Heidelberg, Germany. Part 16, pp. 3291 – 3294.
Berezhnoy D, Gibbs TT, Farb DH (2009) Docking of 1,4-benzodiazepines in the alpha1/gamma2 GABA(A) receptor modulator site. Mol Pharmacol 2009 Aug; 76(2):440-50. PMC 2713131. [Article]
Sadri-Vakili G, Janis GC, Pierce RC, Gibbs TT, Farb DH (2008) Nanomolar Concentrations of Pregnenolone Sulfate Enhance Striatal Dopamine Overflow In Vivo. J Pharmacol Ex Ther 2008 Dec; 327(3): 840-5. PMC 2864155. [Article]
Whittaker MT, Gibbs TT, Farb DH (2008) Pregnenolone sulfate induces NMDA receptor dependent release of dopamine from synaptic terminals in the striatum. J Neurochem. 2008 Oct; 107 (2): 510-21. PMC 2752275. [Press Release]
Berezhnoy D*, Gravielle MC*, Downing S, Kostakis E, Basile AS, Skolnick P, Gibbs TT, Farb DH (2008) Pharmacological Properties of DOV 315,090, an ocinaplon metabolite. BMC Pharmacology, Jun 13; 8:11 (equal contributions: *). PMC 2529273. [Article]
Hu Y, Lund IV, Gravielle MC, Farb DH, Brooks-Kayal AR, Russek SJ (2008) Surface expression of GABA(A) receptors is transcriptionally controlled by the interplay of CREB and its binding partner ICER. J. Biol. Chem. Apr 4; 283 (14):9328-40. Jan 7; Epub 2008 Jan 7. PMC 2431045. [Article]
Berezhnoy D, Gravielle V, Farb DH (2007) Pharmacology of the GABAA Receptor, In: Handbook of Contemporary Neuropharmacology (David Sibley, Michael Kuhar, Israel Hanin, and Phil Skolnick, Eds.) John Wiley & Sons.
Farb DH, Steiger JL, Martin SC, Gravielle MC, Gibbs TT, Russek SJ (2007) Mechanisms of GABAA and GABAB Receptor Gene Expression In: The GABA Receptors (Sam Enna and Hans Mohler, Eds.) Humana Press.
Gibbs TT, Russek SJ, Farb DH. Sulfated steroids as endogenous neuromodulators. Pharmacol Biochem Behav. 2006 Aug;84(4):555-67. Epub 2006 Oct 4. [Abstract]
Popik P, Kostakis E, Krawczyk M, Nowak G, Szewczyk B, Krieter P, Chen Z, Russek SJ, Gibbs TT, Farb DH, Skolnick P, Lippa AS, Basile AS. The anxioselective agent 7-(2-chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methan one (DOV 51892) is more efficacious than diazepam at enhancing GABA-gated currents at alpha1 subunit-containing GABAA receptors. J Pharmacol Exp Ther. 2006 Dec;319(3):1244-52. Epub 2006 Sep 13. [Abstract]
Downing SS, Lee YT, Farb DH, Gibbs TT. Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABA(A) receptors supports an allosteric model of modulation. Br J Pharmacol. 2005 Aug;145(7):894-906. [Abstract]
Lippa A, Czobor P, Stark J, Beer B, Kostakis E, Gravielle M, Bandyopadhyay S, Russek SJ, Gibbs TT, Farb DH, Skolnick P. (2005) Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator. Proc Natl Acad Sci U S A. 2005 May 17;102(20):7380-5. [Abstract]
Gravielle MC, Faris R, Russek SJ, Farb DH. (2005) GABA induces activity dependent delayed-onset uncoupling of GABA/benzodiazepine site interactions in neocortical neurons. J Biol Chem. 2005 Jun 3;280(22):20954-60. [Abstract]
Steiger JL, Bandyopadhyay S, Farb DH, Russek SJ. (2004) cAMP response element-binding protein, activating transcription factor-4, and upstream stimulatory factor differentially control hippocampal GABABR1a and GABABR1b subunit gene expression through alternative promoters. J Neurosci. 2004 Jul 7;24(27):6115-26. [Abstract]
Jang MK, Mierke DF, Russek SJ, Farb DH. (2004) A steroid modulatory domain on NR2B controls N-methyl-D-aspartate receptor proton sensitivity. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8198-203. [Abstract]
Martin SC, Steiger JL, Gravielle MC, Lyons HR, Russek SJ, Farb DH. (2004) Differential expression of gamma-aminobutyric acid type B receptor subunit mRNAs in the developing nervous system and receptor coupling to adenylyl cyclase in embryonic neurons. J Comp Neurol. 2004 May 17;473(1):16-29. [Abstract]
Steiger JL, Alexander MJ, Galler JR, Farb DH, Russek SJ. (2004) Effects of prenatal malnutrition on GABAA receptor alpha1, alpha3 and beta2 mRNA levels. Neuroreport. 2003 Sep 15;14(13):1731-5. [Abstract]
Sadri-Vakili G, Johnson DW, Janis GC, Gibbs TT, Pierce RC, Farb DH. (2003) Inhibition of NMDA-induced striatal dopamine release and behavioral activation by the neuroactive steroid 3alpha-hydroxy-5beta-pregnan-20-one hemisuccinate. J Neurochem. 2003 Jul;86(1):92-101. [Abstract]
Steiger JL, Galler JR, Farb DH, Russek SJ. (2002) Prenatal protein malnutrition reduces beta(2), beta(3) and gamma(2L) GABA(A) receptor subunit mRNAs in the adult septum. Eur J Pharmacol. 2002 Jun 20;446(1-3):201-2. [Abstract]
Malayev A, Gibbs TT, Farb DH. (2002) Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids. Br J Pharmacol. 2002 Feb;135(4):901-9. [Abstract]
Martin SC, Russek SJ, Farb DH. (2001) Human GABA(B)R genomic structure: evidence for splice variants in GABA(B)R1 but not GABA(B)R2. Gene. 2001 Oct 31;278(1-2):63-79. [Abstract]
Lyons HR, Land MB, Gibbs TT, Farb DH. (2001) Distinct signal transduction pathways for GABA-induced GABA(A) receptor down-regulation and uncoupling in neuronal culture: a role for voltage-gated calcium channels. J Neurochem. 2001 Sep;78(5):1114-26. [Abstract]
Gibbs TT, Farb DH. (2000) Dueling enigmas: neurosteroids and sigma receptors in the limelight. Science Signaling 2000 Nov 28;2000(60):PE1. Review. [Abstract]
Russek SJ, Bandyopadhyay S, Farb DH. (2000) An initiator element mediates autologous downregulation of the human type A gamma -aminobutyric acid receptor beta 1 subunit gene. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8600-5. [ Abstract ]
Weaver CE, Land MB, Purdy RH, Richards KG, Gibbs TT, Farb DH. (2000) Geometry and charge determine pharmacological effects of steroids on N-methyl-D-aspartate receptor-induced Ca(2+) accumulation and cell death. J Pharmacol Exp Ther. 2000 Jun;293(3):747-54. [ Abstract ]
McLean PJ, Shpektor D, Bandyopadhyay S, Russek SJ, Farb DH. (2000) A minimal promoter for the GABA(A) receptor alpha6-subunit gene controls tissue specificity. J Neurochem. 2000 May;74(5):1858-69. [ Abstract ]
Lyons HR, Gibbs TT, Farb DH. (2000) Turnover and down-regulation of GABA(A) receptor alpha1, beta2S, and gamma1 subunit mRNAs by neurons in culture. J Neurochem. 2000 Mar;74(3):1041-8. [ Abstract ]
Park-Chung M, Malayev A, Purdy RH, Gibbs TT, Farb DH. (1999) Sulfated and unsulfated steroids modulate gamma-aminobutyric acidA receptor function through distinct sites. Brain Res. 1999 May 29;830(1):72-87. [ Abstract ]
Martin SC, Russek SJ, Farb DH. (1999) Molecular identification of the human GABABR2: cell surface expression and coupling to adenylyl cyclase in the absence of GABABR1. Mol Cell Neurosci. 1999 Mar;13(3):180-91. [ Abstract ]
Weaver CE Jr, Wu FS, Gibbs TT, Farb DH. (1998) Pregnenolone sulfate exacerbates NMDA-induced death of hippocampal neurons. Brain Res. 1998 Aug 24;803(1-2):129-36. [ Abstract ]
Yaghoubi N, Malayev A, Russek SJ, Gibbs TT, Farb DH. (1998) Neurosteroid modulation of recombinant ionotropic glutamate receptors. Brain Res. 1998 Aug 24;803(1-2):153-60. [ Abstract ]
Park-Chung M, Wu FS, Purdy RH, Malayev AA, Gibbs TT, Farb DH. (1997) Distinct sites for inverse modulation of N-methyl-D-aspartate receptors by sulfated steroids. Mol Pharmacol. 1997 Dec;52(6):1113-23. [ Abstract ]
Weaver CE Jr, Marek P, Park-Chung M, Tam SW, Farb DH. (1997) Neuroprotective activity of a new class of steroidal inhibitors of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10450-4. [ Abstract ]
Weaver CE Jr, Park-Chung M, Gibbs TT, Farb DH. (1997) 17beta-Estradiol protects against NMDA-induced excitotoxicity by direct inhibition of NMDA receptors. Brain Res. 1997 Jul 4;761(2):338-41. [ Abstract ]
Laboratory of Molecular Neurobiology in the News
Lab Phone: 617-358-9561