Preserved Calretinin Interneurons in an App Model of Alzheimer’s Disease Disrupt Hippocampal Inhibition via Upregulated P2Y1 Purinoreceptors

Abstract To understand the pathogenesis of specific neuronal circuit dysfunction in Alzheimer’s disease (AD), we investigated the fate of three subclasses of “modulatory interneurons” in hippocampal CA1 using the AppNL-F/NL-F knock-in mouse model of AD. Cholecystokinin- and somatostatin-expressing interneurons were aberrantly hyperactive preceding the presence of the typical AD hallmarks: neuroinflammation and amyloid-β (Aβ) accumulation. These interneurons showed an age-dependent vulnerability to Aβ penetration and a reduction in density and coexpression of the inhibitory neurotransmitter GABA synthesis enzyme, glutamic acid decarboxylase 67 (GAD67), suggesting a loss in their inhibitory function. However, calretinin (CR) interneurons—specialized to govern only inhibition, showed resilience to Aβ accumulation, preservation of structure, and displayed synaptic hyperinhibition, despite the lack of inhibitory control of CA1 excitatory pyramidal cells from midstages of the disease. This aberrant inhibitory homeostasis observed in CA1 CR cells and pyramidal cells was “normalized” by blocking P2Y1 purinoreceptors, which were “upregulated” and strongly expressed in CR cells and astrocytes in AppNL-F/NL-F mice in the later stages of AD. In summary, AD-associated cell-type selective destruction of inhibitory interneurons and disrupted inhibitory homeostasis rectified by modulation of the upregulated purinoreceptor system may serve as a novel therapeutic strategy to normalize selective dysfunctional synaptic homeostasis during pathogenesis of AD.

[1]  Afia B Ali,et al.  Aberrant Excitatory–Inhibitory Synaptic Mechanisms in Entorhinal Cortex Microcircuits During the Pathogenesis of Alzheimer’s Disease , 2019, Cerebral cortex.

[2]  I. Singh,et al.  Pathology of nNOS-Expressing GABAergic Neurons in Mouse Model of Alzheimer’s Disease , 2018, Neuroscience.

[3]  A. Verkhratsky,et al.  Loss of calretinin and parvalbumin positive interneurones in the hippocampal CA1 of aged Alzheimer’s disease mice , 2018, Neuroscience Letters.

[4]  C. Henneberger,et al.  P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model , 2018, The Journal of experimental medicine.

[5]  R. D'Hooge,et al.  Spatial reversal learning defect coincides with hypersynchronous telencephalic BOLD functional connectivity in APPNL-F/NL-F knock-in mice , 2018, Scientific Reports.

[6]  M. Walker,et al.  Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model , 2018, British journal of pharmacology.

[7]  P. Alifragis,et al.  Synaptic dysfunction in Alzheimer's disease: the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention , 2018, Neural regeneration research.

[8]  H. Wille,et al.  Somatostatin in Alzheimer's disease: A new Role for an Old Player , 2018, Prion.

[9]  S. Duan,et al.  Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons , 2017, Nature Communications.

[10]  L. Mucke,et al.  Network abnormalities and interneuron dysfunction in Alzheimer disease , 2016, Nature Reviews Neuroscience.

[11]  J. Wu,et al.  A novel mechanism of memory loss in Alzheimer’s disease mice via the degeneration of entorhinal–CA1 synapses , 2016, Molecular Psychiatry.

[12]  M. Kossut,et al.  Somatostatin and Somatostatin-Containing Neurons in Shaping Neuronal Activity and Plasticity , 2016, Front. Neural Circuits.

[13]  S. A. Hussaini,et al.  Neuronal activity enhances tau propagation and tau pathology in vivo , 2016, Nature Neuroscience.

[14]  G. Cox,et al.  Hyperactive Somatostatin Interneurons Contribute to Excitotoxicity in Neurodegenerative Disorders , 2016, Nature Neuroscience.

[15]  A. Martínez-Marcos,et al.  Interneurons, tau and amyloid-β in the piriform cortex in Alzheimer’s disease , 2015, Brain Structure and Function.

[16]  Lief E. Fenno,et al.  Chronic optogenetic activation augments Aβ pathology in a mouse model of Alzheimer disease , 2022 .

[17]  O. Garaschuk,et al.  Neuroinflammation in Alzheimer's disease , 2015, The Lancet Neurology.

[18]  Marco Foddis,et al.  Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model , 2014, Nature Communications.

[19]  Yong Jeong,et al.  GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease , 2014, Nature Medicine.

[20]  Jochen F. Staiger,et al.  Revisiting enigmatic cortical calretinin-expressing interneurons , 2014, Front. Neuroanat..

[21]  S. Itohara,et al.  Single App knock-in mouse models of Alzheimer's disease , 2014, Nature Neuroscience.

[22]  K. Deisseroth,et al.  Dendritic Inhibition Provided by Interneuron-Specific Cells Controls the Firing Rate and Timing of the Hippocampal Feedback Inhibitory Circuitry , 2014, The Journal of Neuroscience.

[23]  D. Holtzman,et al.  Neuronal activity regulates extracellular tau in vivo , 2014, The Journal of experimental medicine.

[24]  R. Mayeux,et al.  Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease , 2013, Nature Neuroscience.

[25]  Yadong Huang,et al.  Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice , 2012, PloS one.

[26]  B. Austen,et al.  Amyloid-β Acts as a Regulator of Neurotransmitter Release Disrupting the Interaction between Synaptophysin and VAMP2 , 2012, PloS one.

[27]  Kelly O'Keefe,et al.  Hippocampal Hyperactivation Associated with Cortical Thinning in Alzheimer's Disease Signature Regions in Non-Demented Elderly Adults , 2011, The Journal of Neuroscience.

[28]  J. Morris,et al.  Alzheimer’s Disease: The Challenge of the Second Century , 2011, Science Translational Medicine.

[29]  C. Kilkenny,et al.  Guidelines for reporting experiments involving animals: the ARRIVE guidelines , 2010, British journal of pharmacology.

[30]  L. Mucke,et al.  Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks , 2010, Nature Neuroscience.

[31]  I. Slutsky,et al.  Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses , 2009, Nature Neuroscience.

[32]  M. Luca,et al.  Faculty Opinions recommendation of Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. , 2009 .

[33]  Shaomin Li,et al.  Soluble Oligomers of Amyloid β Protein Facilitate Hippocampal Long-Term Depression by Disrupting Neuronal Glutamate Uptake , 2009, Neuron.

[34]  B. Hyman,et al.  Synchronous Hyperactivity and Intercellular Calcium Waves in Astrocytes in Alzheimer Mice , 2009, Science.

[35]  Arthur Konnerth,et al.  Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease , 2008, Science.

[36]  Ilya Bezprozvanny,et al.  Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease , 2008, Trends in Neurosciences.

[37]  P. Somogyi,et al.  Neuronal Diversity and Temporal Dynamics: The Unity of Hippocampal Circuit Operations , 2008, Science.

[38]  Anatol C. Kreitzer,et al.  Aberrant Excitatory Neuronal Activity and Compensatory Remodeling of Inhibitory Hippocampal Circuits in Mouse Models of Alzheimer's Disease , 2007, Neuron.

[39]  R. Rissman,et al.  GABAA receptors in aging and Alzheimer’s disease , 2007, Journal of neurochemistry.

[40]  Afia B Ali,et al.  Presynaptic Inhibition of GABAA receptor-mediated unitary IPSPs by cannabinoid receptors at synapses between CCK-positive interneurons in rat hippocampus. , 2007, Journal of neurophysiology.

[41]  Kim N. Green,et al.  Intracellular amyloid-β in Alzheimer's disease , 2007, Nature Reviews Neuroscience.

[42]  Khaleel Bhaukaurally,et al.  Glutamate exocytosis from astrocytes controls synaptic strength , 2007, Nature Neuroscience.

[43]  L. Mucke,et al.  A network dysfunction perspective on neurodegenerative diseases , 2006, Nature.

[44]  Steven Mennerick,et al.  Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo , 2005, Neuron.

[45]  M. Higuchi,et al.  Somatostatin regulates brain amyloid β peptide Aβ42 through modulation of proteolytic degradation , 2005, Nature Medicine.

[46]  Kazuhide Inoue,et al.  Direct Excitation of Inhibitory Interneurons by Extracellular ATP Mediated by P2Y1 Receptors in the Hippocampal Slice , 2004, The Journal of Neuroscience.

[47]  B. Khakh,et al.  ATP Excites Interneurons and Astrocytes to Increase Synaptic Inhibition in Neuronal Networks , 2004, The Journal of Neuroscience.

[48]  S. Gobbo,et al.  Neuronal Synchrony Mediated by Astrocytic Glutamate through Activation of Extrasynaptic NMDA Receptors , 2004, Neuron.

[49]  R. Malinow,et al.  APP Processing and Synaptic Function , 2003, Neuron.

[50]  N Kopell,et al.  Gap Junctions between Interneuron Dendrites Can Enhance Synchrony of Gamma Oscillations in Distributed Networks , 2001, The Journal of Neuroscience.

[51]  Helen J. Cross,et al.  A Possible Role for Gap Junctions in Generation of Very Fast EEG Oscillations Preceding the Onset of, and Perhaps Initiating, Seizures , 2001, Epilepsia.

[52]  R. Mckernan,et al.  Density and pharmacology of α5 subunit-containing GABAA receptors are preserved in hippocampus of Alzheimer’s disease patients , 2000, Neuroscience.

[53]  H. Soininen,et al.  Subfield- and layer-specific changes in parvalbumin, calretinin and calbindin-D28k immunoreactivity in the entorhinal cortex in Alzheimer's disease , 1999, Neuroscience.

[54]  L. Acsády,et al.  Postsynaptic targets of somatostatin-immunoreactive interneurons in the rat hippocampus , 1999, Neuroscience.

[55]  Peter Lipp,et al.  Calcium - a life and death signal , 1998, Nature.

[56]  J. Deuchars,et al.  CA1 pyramidal to basket and bistratified cell EPSPs: dual intracellular recordings in rat hippocampal slices , 1998, The Journal of physiology.

[57]  T. Freund,et al.  Interneurons Containing Calretinin Are Specialized to Control Other Interneurons in the Rat Hippocampus , 1996, The Journal of Neuroscience.

[58]  E. Soriano,et al.  Calretinin-immunoreactive neurons in the normal human temporal cortex and in Alzheimer's disease , 1995, Brain Research.

[59]  J. McLaurin,et al.  Hippocampal GABAergic neurons are susceptible to amyloid-β toxicity in vitro and are decreased in number in the Alzheimer's disease TgCRND8 mouse model. , 2012, Journal of Alzheimer's disease : JAD.

[60]  F. LaFerla,et al.  Intracellular amyloid-beta in Alzheimer's disease. , 2007, Nature reviews. Neuroscience.