Deficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice

Synapse degeneration is an early and invariant feature of neurodegenerative diseases. Indeed, synapse loss occurs prior to neuronal degeneration and correlates with the symptom severity of these diseases. However, the molecular mechanisms that trigger synaptic loss remain poorly understood. Here we demonstrate that deficient Wnt signalling elicits synaptic degeneration in the adult striatum. Inducible expression of the secreted Wnt antagonist Dickkopf1 (Dkk1) in adult mice (iDkk1) decreases the number of cortico-striatal glutamatergic synapses and of D1 and D2 dopamine receptor clusters. Synapse loss occurs in the absence of axon retraction or cell death. The remaining excitatory terminals contain fewer synaptic vesicles and have a reduced probability of evoked transmitter release. IDkk1 mice show impaired motor coordination and are irresponsive to amphetamine. These studies identify Wnts as key endogenous regulators of synaptic maintenance and suggest that dysfunction in Wnt signalling contributes to synaptic degeneration at early stages in neurodegenerative diseases.

[1]  Hans Clevers,et al.  Wnt/β-Catenin Signaling and Disease , 2012, Cell.

[2]  Andrea Caricasole,et al.  Induction of the Wnt Inhibitor, Dickkopf‐1, Is Associated with Neurodegeneration Related to Temporal Lobe Epilepsy , 2007, Epilepsia.

[3]  Yan Li,et al.  LDL-receptor-related protein 6 is a receptor for Dickkopf proteins , 2001, Nature.

[4]  D. Sulzer,et al.  Mechanisms of neurotransmitter release by amphetamines: A review , 2005, Progress in Neurobiology.

[5]  L. Raymond,et al.  Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease , 2010, Trends in Neurosciences.

[6]  T. Svitkina,et al.  Improved procedures for electron microscopic visualization of the cytoskeleton of cultured cells. , 1995, Journal of structural biology.

[7]  Santiago Canals,et al.  Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. , 2003, Human molecular genetics.

[8]  Henry H Yin,et al.  Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[9]  S. Tonegawa,et al.  Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice , 1994, Cell.

[10]  K. Fukunaga,et al.  Immunohistochemical Localization of Ca2+/Calmodulin‐Dependent Protein Kinase II in Rat Brain and Various Tissues , 1988, Journal of neurochemistry.

[11]  P. Salinas.  Wnt signaling in the vertebrate central nervous system: from axon guidance to synaptic function. , 2012, Cold Spring Harbor perspectives in biology.

[12]  R. Nicoll,et al.  Increased Expression of α-Synuclein Reduces Neurotransmitter Release by Inhibiting Synaptic Vesicle Reclustering after Endocytosis , 2010, Neuron.

[13]  L. Lanfumey,et al.  Parkin-Knockout Mice did not Display Increased Vulnerability to Intranasal Administration of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) , 2013, Neurotoxicity Research.

[14]  S. Millar,et al.  WNT signals are required for the initiation of hair follicle development. , 2002, Developmental cell.

[15]  Kristen M Harris,et al.  Coordination of size and number of excitatory and inhibitory synapses results in a balanced structural plasticity along mature hippocampal CA1 dendrites during LTP , 2011, Hippocampus.

[16]  M. Chesselet,et al.  Synaptogenesis and ultrastructural localization of the polysialylated neural cell adhesion molecule in the developing striatum , 1999, The Journal of comparative neurology.

[17]  A. Holtmaat,et al.  Evidence for a Role of the Chemorepellent Semaphorin III and Its Receptor Neuropilin-1 in the Regeneration of Primary Olfactory Axons , 1998, The Journal of Neuroscience.

[18]  T. Belenkaya,et al.  The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network. , 2008, Developmental cell.

[19]  P. Salinas,et al.  The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss , 2012, The Journal of Neuroscience.

[20]  E. Arenas,et al.  Emerging roles of Wnts in the adult nervous system , 2010, Nature Reviews Neuroscience.

[21]  V. Budnik,et al.  Wnt signaling during synaptic development and plasticity , 2011, Current Opinion in Neurobiology.

[22]  J. Jankovic,et al.  The VPS35 gene and Parkinson's disease , 2013, Movement disorders : official journal of the Movement Disorder Society.

[23]  Aubin Michalon,et al.  Inducible and neuron‐specific gene expression in the adult mouse brain with the rtTA2S‐M2 system , 2005, Genesis.

[24]  Richard Wade-Martins,et al.  Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model , 2013, Proceedings of the National Academy of Sciences.

[25]  E. Aronica,et al.  Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Associated with Neuronal Degeneration in Alzheimer's Brain , 2004, The Journal of Neuroscience.

[26]  M. Ehlers,et al.  Pruning and loss of excitatory synapses by the parkin ubiquitin ligase , 2008, Proceedings of the National Academy of Sciences.

[27]  C. Niehrs,et al.  Function and biological roles of the Dickkopf family of Wnt modulators , 2006, Oncogene.

[28]  T. Schikorski,et al.  Quantitative Ultrastructural Analysis of Hippocampal Excitatory Synapses Materials and Methods Terminology Fixation and Embedding , 2022 .

[29]  H. Korswagen,et al.  Wnt Gradient Formation Requires Retromer Function in Wnt-Producing Cells , 2006, Science.

[30]  D. Surmeier,et al.  D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons , 2007, Trends in Neurosciences.

[31]  P. Salinas,et al.  Signalling in neural development: WNTS in the vertebrate nervous system: from patterning to neuronal connectivity , 2005, Nature Reviews Neuroscience.

[32]  A. Pisani,et al.  Aberrant striatal synaptic plasticity in monogenic parkinsonisms , 2012, Neuroscience.

[33]  Z. F. H. Cao,et al.  Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response , 2009, Annals of neurology.

[34]  Y. Smith,et al.  The thalamostriatal system: a highly specific network of the basal ganglia circuitry , 2004, Trends in Neurosciences.

[35]  D. Walsh,et al.  Alzheimer's disease: synaptic dysfunction and Aβ , 2009, Molecular Neurodegeneration.

[36]  K. Shen,et al.  Guidance molecules in synapse formation and plasticity. , 2010, Cold Spring Harbor perspectives in biology.

[37]  B. Yamamoto,et al.  The Basal Ganglia as a Substrate for the Multiple Actions of Amphetamines. , 2011, Basal ganglia.

[38]  A. Björklund,et al.  Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons , 2012, Proceedings of the National Academy of Sciences.

[39]  M. Hayden,et al.  Cognitive Dysfunction Precedes Neuropathology and Motor Abnormalities in the YAC128 Mouse Model of Huntington's Disease , 2005, The Journal of Neuroscience.

[40]  Rosa M. Sancho,et al.  Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways , 2009, Human molecular genetics.

[41]  Y. Smith,et al.  Striatal Spine Plasticity in Parkinson's Disease , 2010, Front. Neuroanat..

[42]  D. Sulzer,et al.  Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. , 2000, Neuron.

[43]  Heidi Phillips,et al.  Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System , 2000, Neuron.

[44]  A. Zorn,et al.  Wnt signalling: Antagonistic Dickkopfs , 2001, Current Biology.

[45]  A. Pisani,et al.  Impaired dopamine release and synaptic plasticity in the striatum of Parkin−/− mice , 2009, Journal of neurochemistry.

[46]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[47]  J. Paul Bolam,et al.  Cortical and Thalamic Innervation of Direct and Indirect Pathway Medium-Sized Spiny Neurons in Mouse Striatum , 2010, The Journal of Neuroscience.

[48]  M. Kennedy,et al.  Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[49]  M. Saarma,et al.  In heterozygous GDNF knockout mice the response of striatal dopaminergic system to acute morphine is altered , 2006, Synapse.

[50]  D. Lovinger,et al.  Genetic Inhibition of CaMKII in Dorsal Striatal Medium Spiny Neurons Reduces Functional Excitatory Synapses and Enhances Intrinsic Excitability , 2012, PloS one.

[51]  Tapan P. Patel,et al.  Exogenous α-Synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death , 2011, Neuron.

[52]  S. Millar,et al.  Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis , 2004, Development.

[53]  D. Lovinger,et al.  Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill , 2009, Nature Neuroscience.

[54]  Andrea Caricasole,et al.  Induction of the Wnt Antagonist, Dickkopf-1, Contributes to the Development of Neuronal Death in Models of Brain Focal Ischemia , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[55]  E. Kandel,et al.  Inducible and Reversible Gene Expression with the rtTA System for the Study of Memory , 1998, Neuron.

[56]  A. Saiardi,et al.  Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[57]  I. Sora,et al.  Cocaine, reward, movement and monoamine transporters , 2002, Molecular Psychiatry.