Laboratory of Molecular Neurobiology
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. Drs. David Farb and Marcia Ratner of the Laboratory of Molecular Neurobiology were one of the first teams of investigators to successfully use in vivo electrophysiological techniques to advance our understanding of how systemically administered drugs modulate neural network activities implicated in memory deficits associated with age-related amnestic mild cognitive impairment (Hippocampus, 2015) and Alzheimer’s disease (Heliyon, 2021). The work of Drs. Farb and Ratner is advancing the use of in vivo electrophysiology as an applied science in preclinical neurotoxicology research (Frontiers in Toxicology, 2022).
Silicon Probe Microelectrodes
The Laboratory is currently using this same technology combined with ultra fine silicon microelectrode arrays (see figures and video below) to identify subregion specific 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 electrode layouts, silicon microelectrode arrays permit for recording across strata within a hippocampal subregion and, from more than one subregion (e.g. dentate gyrus, CA3 and CA1). Long single shank silicon probes such as the one pictured below permit recording from multiple hippocampal subregions with different current sources and sinks.
The figures below demonstrate how local field potentials are recorded and visualized for analysis. Single unit activity associated with high frequency (140 to 200 Hz) sharp wave ripples in the CA1 hippocampal subregion are shown inside box in lower figure. Real-time recordings of ripples with associate action potential “spikes” are shown in the video below titled “Recording of Ripples and Action Potential Spikes in Real-Time“. The data shown in this video were acquired using a 4 shank 32 electrode silicon microlectrode array while the animal was awake and immobile in a familiar environment as reported in our paper published in Cell Press Heliyon, 2021. 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 Multiple Unit Activity
Silicon Probe Microelectrode Arrays
Recording of Ripples and Action Potential Spikes in Real-Time
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 Video
Place 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 remapping video below.
The place fields of a rat “remapping” when the animal is moved from a familiar square environment to a novel cylindrical one is shown in the figure below. The activity of these place cells is altered by aging and diseases. Place cell activity can also be modulated with drugs (e.g., 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.
Tetrode Array Construction
Observations and Results
Combined Administration of Levetiracetam and Valproic Acid Increases Spatial Information Content Per Spike in Aged Rat Hippocampal Place Cells
The Laboratory has 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).
Prodromal dysfunction of α5GABA-A receptors in the TgF344-AD rat model of Alzheimer’s disease
Bioaccumulation of amyloid beta (Aβ) peptides is implicated in Alzheimer’s disease. Animal models over-expressing Aβ show memory deficits. Hippocampal sharp-wave ripples (140 to 200 Hz) have been implicated in memory consolidation. Disruption of these high frequency oscillations produces memory deficits. Compounds that decrease tonic inhibition mediated by α5 type GABA receptors improve memory function in healthy rodents. Administration of the putative cognitive enhancer α5IA which acts as a negative allosteric modulator of α5 type GABAA receptors increases peak ripple amplitudes in wild type adult male rats but has no effect on peak ripple amplitudes in adult male TgF344-AD rats which show elevated plasma concentrations of Aβ42 and Aβ40 (Heliyon, 2021). (see results of these experiments below).
Administration of α5IA does not increase ripple band power or peak ripple amplitude in TgF344-AD Rats. A) Comparison of the spectrums (top panel) from representative well-positioned electrodes in two male F344s age 9 & 18 mo reveals a remarkable overt increase in ripple band power following administration of α5IA (1.0 mg/kg). B) Power spectrums from well-positioned tetrodes adult male TgF344-AD rats age 9–15 months demonstrates a decrease in ripple band power following administration of α5IA. C. Histogram showing percent increase in ripple band power in F344 rats following administration of escalating doses of α5IA. D) Percent decrease in ripple band power in TgF344-AD rats following administration of escalating doses of α5IA. E) Percent decrease in ripple band power in adult F344 rats following administration of vehicle only during serial exposures to a familiar environment. F) Peak ripple amplitude frequency distributions in F344 before and after oral administration of 1.0 mg/kg α5IA (n . 3) show a shift to the right that is not seen in TgF344-AD rats (n . 3). G) Peak ripple amplitude increases in F344 rats following 1.0 mg/kg α5IA. In addition, peak ripple amplitude is significantly greater under vehicle conditions in TgF344-AD rats as compared with wild type F344s. Significance: * at p < 0.05, **p < 0.01, and ***p < 0.001.
Current Laboratory Members
David H. Farb, Ph.D.
Professor of Pharmacology; Director of the NIGMS Training Program in BioMolecular Pharmacology
Senior Laboratory Members
Vidhya Kumaresan, Ph.D.
Research Assistant Professor of Pharmacology
Marcia H. Ratner, Ph.D., DABT
Assistant Professor of Pharmacology
Select Publications and Abstracts
Ratner M, Downing S, Guo O, Odamah KA, Stewart T, Kumaresan V, Xia W, Farb D. Role of Pharmacological Modulation of Tonic Inhibition in Hippocampal Sharp Wave Ripples Amplitude and Place Cell Firing Dynamics. FASEB J. 2022 May; 36 Suppl 1. [Abstract]
Ratner MH, Farb DH. Probing the Neural Circuitry Targets of Neurotoxicants In Vivo Through High Density Silicon Probe Brain Implants. Front Toxicol. 2022; 4:836427.[Article]
Tipton AE, George J, Ratner M, Farb D, Russek S. Data from single nuclei RNA-sequencing reveals a prodromal gene network response in excitatory neurons of a humanized rat Alzheimer’s disease model. Alzheimer’s & Dementia. 2021; (17 Suppl 2):e058589. [Abstract]
Ratner MH, Downing S, Guo O, Odamah KA, Stewart TM, Kumaresan V, Xia W, Farb DH: Loss of tonic inhibitory control of sharp wave ripples in the TgF344-AD rat. Program/Poster No. P232.10. Presented at the Society for Neuroscience Annual Meeting, November 2021.[Abstract]
Ratner MH, Downing S, Guo O, Odamah KA, Stewart TM, Kumaresan V, Xia W, Farb DH: Does Modulation of Tonic Inhibition Control Sharp Wave Ripples and Hippocampal Place Cell Dynamics? Program/Poster No. P234.02. Presented at the Society for Neuroscience Annual Meeting, November 2021.[Abstract]
Ratner MH, Downing SS, Guo O, Odamah KE, Stewart TM, Kumaresan V, Robitsek RJ, Xia W, Farb DH. Prodromal dysfunction of α5GABA-A receptor modulated hippocampal ripples occurs prior to neurodegeneration in the TgF344-AD rat model of Alzheimer’s disease. Heliyon, September 2021, 7(9): e07895. [Article]
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] * Co-First Authors.
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 ]
Lab Phone: 617-358-9561