References
Ali AB (2007). Presynaptic Inhibition of GABAA receptor-mediated unitary
IPSPs by cannabinoid receptors at synapses between CCK-positive
interneurons in rat hippocampus. Journal of neurophysiology 98:861-869.
Ali AB, et al. (2006). Distinct Ca2+ channels mediate transmitter
release at excitatory synapses displaying different dynamic properties
in rat neocortex. Cerebral cortex 16: 386-393.
Ali AB, et al. (2008). Synaptic alpha 5 subunit-containing GABAA
receptors mediate IPSPs elicited by dendrite-preferring cells in rat
neocortex. Cerebral cortex 18: 1260-1271.
Araujo F, et al. (1999). Native gamma-aminobutyric acid type A
receptors from rat hippocampus, containing both alpha 1 and alpha 5
subunits, exhibit a single benzodiazepine binding site with alpha 5
pharmacological properties. The Journal of pharmacology and experimental
therapeutics 290: 989-997.
Atack JR (2010). Preclinical and clinical pharmacology of the GABAA
receptor alpha5 subtype-selective inverse agonist alpha5IA. Pharmacology
& therapeutics 125: 11-26.
Atack JR, et al. (2006). L-655,708 enhances cognition in rats but
is not proconvulsant at a dose selective for alpha5-containing GABAA
receptors. Neuropharmacology 51: 1023-1029.
Atack JR, et al. (2009). In vitro and in vivo properties of
3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-
pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor
alpha5 subtype-selective inverse agonist. The Journal of pharmacology
and experimental therapeutics 331: 470-484.
Ballard TM, et al. (2009). RO4938581, a novel cognitive enhancer
acting at GABAA alpha5 subunit-containing receptors. Psychopharmacology
202: 207-223.
Becker JT, et al. (1980). Neuroanatomical bases of spatial
memory. Brain research 200: 307-320.
Braudeau J, et al. (2011). Specific targeting of the GABA-A
receptor alpha5 subtype by a selective inverse agonist restores
cognitive deficits in Down syndrome mice. J Psychopharmacol 25:1030-1042.
Brown LE, et al. (2016). gamma-Aminobutyric Acid Type A (GABAA)
Receptor Subunits Play a Direct Structural Role in Synaptic Contact
Formation via Their N-terminal Extracellular Domains. J Biol Chem
291: 13926-13942.
Brunig I, et al. (2002). Intact sorting, targeting, and
clustering of gamma-aminobutyric acid A receptor subtypes in hippocampal
neurons in vitro. J Comp Neurol 443: 43-55.
Caraiscos VB, et al. (2004). Tonic inhibition in mouse
hippocampal CA1 pyramidal neurons is mediated by alpha5
subunit-containing gamma-aminobutyric acid type A receptors. Proceedings
of the National Academy of Sciences of the United States of America
101: 3662-3667.
Chambers MS, et al. (2003). Identification of a novel, selective
GABA(A) alpha5 receptor inverse agonist which enhances cognition.
Journal of medicinal chemistry 46: 2227-2240.
Chung H, et al. (2020). Dissociation of somatostatin and
parvalbumin interneurons circuit dysfunctions underlying hippocampal
theta and gamma oscillations impaired by amyloid beta oligomers in vivo.
Brain Struct Funct 225: 935-954.
Collinson N, et al. (2006). An inverse agonist selective for
alpha5 subunit-containing GABAA receptors improves encoding and recall
but not consolidation in the Morris water maze. Psychopharmacology
188: 619-628.
Collinson N, et al. (2002). Enhanced learning and memory and
altered GABAergic synaptic transmission in mice lacking the alpha 5
subunit of the GABAA receptor. The Journal of neuroscience : the
official journal of the Society for Neuroscience 22: 5572-5580.
Crestani F, et al. (2002). Trace fear conditioning involves
hippocampal alpha5 GABA(A) receptors. Proceedings of the National
Academy of Sciences of the United States of America 99:8980-8985.
Cutsuridis V, et al. (2009). Hippocampus, microcircuits and
associative memory. Neural Netw 22: 1120-1128.
Dawson GR, et al. (2006). An inverse agonist selective for alpha5
subunit-containing GABAA receptors enhances cognition. The Journal of
pharmacology and experimental therapeutics 316: 1335-1345.
Duchon JM, et al. (2019). Safety and Varicella Outcomes in In
Utero-Exposed Newborns and Preterm Infants Treated With Varicella Zoster
Immune Globulin (VARIZIG): A Subgroup Analysis of an Expanded-Access
Program. J Pediatric Infect Dis Soc.
Eimerbrink MJ, et al. (2019). The alpha5-GABAAR inverse agonist
MRK-016 upregulates hippocampal BDNF expression and prevents cognitive
deficits in LPS-treated mice, despite elevations in hippocampal Abeta.
Behav Brain Res 359: 871-877.
Fonseca M, et al. (1995). Calretinin-immunoreactive neurons in
the normal human temporal cortex and in Alzheimer’s disease. Brain
research 691: 83-91.
Fuchs C, et al. (2013). GABA(A) receptors can initiate the
formation of functional inhibitory GABAergic synapses. Eur J Neurosci
38: 3146-3158.
Ghafari M, et al. (2017). Formation of GABAA receptor complexes
containing alpha1 and alpha5 subunits is paralleling a multiple T-maze
learning task in mice. Brain Struct Funct 222: 549-561.
Glykys J, et al. (2008). Which GABA(A) receptor subunits are
necessary for tonic inhibition in the hippocampus? The Journal of
neuroscience : the official journal of the Society for Neuroscience
28: 1421-1426.
Goodkin HP, et al. (2007). GABA(A) receptor internalization
during seizures. Epilepsia 48 Suppl 5: 109-113.
Gulyas AI, et al. (1996). Interneurons containing calretinin are
specialized to control other interneurons in the rat hippocampus. The
Journal of neuroscience : the official journal of the Society for
Neuroscience 16: 3397-3411.
Haefely WE, et al. (1993). The multiplicity of actions of
benzodiazepine receptor ligands. Canadian journal of psychiatry Revue
canadienne de psychiatrie 38 Suppl 4: S102-108.
Howell O, et al. (2000). Density and pharmacology of alpha5
subunit-containing GABA(A) receptors are preserved in hippocampus of
Alzheimer’s disease patients. Neuroscience 98: 669-675.
Iball J, et al. (2011). Endocannabinoid Release Modulates
Electrical Coupling between CCK Cells Connected via Chemical and
Electrical Synapses in CA1. Frontiers in neural circuits 5: 17.
Katona I, et al. (1999). Postsynaptic targets of
somatostatin-immunoreactive interneurons in the rat hippocampus.
Neuroscience 88: 37-55.
Khan AA, et al. (2018). Cannabidiol exerts antiepileptic effects
by restoring hippocampal interneuron functions in a temporal lobe
epilepsy model. Br J Pharmacol.
Leao RN, et al. (2012). OLM interneurons differentially modulate
CA3 and entorhinal inputs to hippocampal CA1 neurons. Nature
neuroscience 15: 1524-1530.
Liu R, et al. (1996). Synthesis and pharmacological properties of
novel 8-substituted imidazobenzodiazepines: high-affinity, selective
probes for alpha 5-containing GABAA receptors. Journal of medicinal
chemistry 39: 1928-1934.
Magnin E, et al. (2019). Input-Specific Synaptic Location and
Function of the alpha5 GABAA Receptor Subunit in the Mouse CA1
Hippocampal Neurons. The Journal of neuroscience : the official journal
of the Society for Neuroscience 39: 788-801.
Martinez-Cue C, et al. (2014). Treating enhanced GABAergic
inhibition in Down syndrome: use of GABA alpha5-selective inverse
agonists. Neurosci Biobehav Rev 46 Pt 2: 218-227.
McGrath JC, et al. (2010). Guidelines for reporting experiments
involving animals: the ARRIVE guidelines. Br J Pharmacol 160:1573-1576.
McKernan RM, et al. (1996). Which GABAA-receptor subtypes really
occur in the brain? Trends Neurosci 19: 139-143.
Mohler H, et al. (2002). A new benzodiazepine pharmacology. The
Journal of pharmacology and experimental therapeutics 300: 2-8.
Munakata M, et al. (1998). Temperature-dependent effect of
zolpidem on the GABAA receptor-mediated response at recombinant human
GABAA receptor subtypes. Brain research 807: 199-202.
Petrache AL, et al. (2019). Aberrant Excitatory-Inhibitory
Synaptic Mechanisms in Entorhinal Cortex Microcircuits During the
Pathogenesis of Alzheimer’s Disease. Cerebral cortex 29:1834-1850.
Price JL, et al. (2001). Neuron number in the entorhinal cortex
and CA1 in preclinical Alzheimer disease. Arch Neurol 58:1395-1402.
Quirk K, et al. (1996). [3H]L-655,708, a novel ligand
selective for the benzodiazepine site of GABAA receptors which contain
the alpha 5 subunit. Neuropharmacology 35: 1331-1335.
Rissman RA, et al. (2007). GABA(A) receptors in aging and
Alzheimer’s disease. J Neurochem 103: 1285-1292.
Roche clinical trial for Basmisanil (RO5186582) started in 2016 and
finished in 2019, Clinical Trials US
website https://clinicaltrials.gov/ct2/show/NCT02953639
Saito T, et al. (2014). Single App knock-in mouse models of
Alzheimer’s disease. Nature neuroscience 17: 661-663.
Sasaguri H, et al. (2017). APP mouse models for Alzheimer’s
disease preclinical studies. EMBO J 36: 2473-2487.
Savic MM, et al. (2008). PWZ-029, a compound with moderate
inverse agonist functional selectivity at GABA(A) receptors containing
alpha5 subunits, improves passive, but not active, avoidance learning in
rats. Brain research 1208: 150-159.
Scimemi A, et al. (2005). Multiple and plastic receptors mediate
tonic GABAA receptor currents in the hippocampus. The Journal of
neuroscience : the official journal of the Society for Neuroscience
25: 10016-10024.
Serwanski DR, et al. (2006). Synaptic and nonsynaptic
localization of GABAA receptors containing the alpha5 subunit in the rat
brain. J Comp Neurol 499: 458-470.
Shi A, et al. (2019). Preserved Calretinin Interneurons in an App
Model of Alzheimer’s Disease Disrupt Hippocampal Inhibition via
Upregulated P2Y1 Purinoreceptors. Cerebral cortex.
Sieghart W (1995). Structure and pharmacology of gamma-aminobutyric
acidA receptor subtypes. Pharmacological reviews 47: 181-234.
Sieghart W, et al. (2002). Subunit composition, distribution and
function of GABA(A) receptor subtypes. Curr Top Med Chem 2:795-816.
Sternfeld F, et al. (2004). Selective, orally active
gamma-aminobutyric acidA alpha5 receptor inverse agonists as cognition
enhancers. Journal of medicinal chemistry 47: 2176-2179.
Sung K, Lee A-R, (1992) Synthesis of
[(4,5‐disubstituted‐4H ‐1,2,4‐triazol‐3‐yl)thio]alkanoic acids
and their analogues as possible antiinflammatory agents J. Het.
Chem ., 29 , 1101-1109.
Tort AB, et al. (2007). On the formation of gamma-coherent cell
assemblies by oriens lacunosum-moleculare interneurons in the
hippocampus. Proceedings of the National Academy of Sciences of the
United States of America 104: 13490-13495.
Whiting PJ (2003). The GABAA receptor gene family: new opportunities for
drug development. Curr Opin Drug Discov Devel 6: 648-657.
Yee BK, et al. (2004). GABA receptors containing the alpha5
subunit mediate the trace effect in aversive and appetitive conditioning
and extinction of conditioned fear. Eur J Neurosci 20:1928-1936.
Zhang W, et al. (2016). Hyperactive somatostatin interneurons
contribute to excitotoxicity in neurodegenerative disorders. Nat
Neurosci 19: 557-559.
Author contribution:
Alexandra L. Petrache – Performed immunofluorescence studies on mouse
brains to characterise the expression of α5 GABAARs in
different subtypes of interneurons, and assisted in preparing the
manuscript.
Archie A. Khan- Designed and produced the new alpha 5 cell line and
assisted in preparing the manuscript.
Alessandra Monaco – Synthesised and refined various analogues of alpha
5 NAMs with varying biological activity.
Martin W. Nicholson – Designed and produced the
α5β2γ2-GABAAR stable cell line.
Martyna Kuta-Siejkowska - performed molecular docking and identification
of the final conformation of the developed NAM.
Shozeb Haider - Computational modelling and assisted in preparing the
manuscript.
Stephen Hilton – Developed, refined and synthesised the α5 compounds.
Jasmina N. Jovanovic – Supervised production and characterisation of
all HEK293 cell lines stably expressing GABAARs which
were used in this study.
Afia .B Ali – Designed and coordinated the project, performed and
analysed all electrophysiology and neuroanatomy experiments, and
prepared the manuscript.