The Schizophrenia Susceptibility Gene dysbindin Controls Synaptic Homeostasis

Dysbindin Function in Synaptic Homeostasis Homeostatic signaling systems are widely believed to stabilize neural function over prolonged periods of time. However, the molecular mechanisms of homeostatic signaling in the nervous system are largely unknown, and direct links between defective homeostatic signaling and disease-causing genes remain obscure. Dickman and Davis (p. 1127) performed a large-scale, electrophysiology-based genetic screen for mutations that specifically disrupt synaptic homeostasis. DTNBP1 is one of two genes that are most strongly and consistently associated with schizophrenia susceptibility in humans. The Drosophila homolog of DTNBP1 (dysbindin) was identified in the screen and was found to function during synapse development, baseline neurotransmission, and synaptic homeostasis. Dysbindin altered the calcium-dependence of vesicle release and was essential in the presynaptic neuron for both the induction and expression of synaptic homeostasis. The dysbindin protein is required for the modulation of presynaptic neurotransmitter release in Drosophila. The molecular mechanisms that achieve homeostatic stabilization of neural function remain largely unknown. To better understand how neural function is stabilized during development and throughout life, we used an electrophysiology-based forward genetic screen and assessed the function of more than 250 neuronally expressed genes for a role in the homeostatic modulation of synaptic transmission in Drosophila. This screen ruled out the involvement of numerous synaptic proteins and identified a critical function for dysbindin, a gene linked to schizophrenia in humans. We found that dysbindin is required presynaptically for the retrograde, homeostatic modulation of neurotransmission, and functions in a dose-dependent manner downstream or independently of calcium influx. Thus, dysbindin is essential for adaptive neural plasticity and may link altered homeostatic signaling with a complex neurological disease.

[1]  C. Goodman,et al.  Genetic Analysis of Glutamate Receptors in Drosophila Reveals a Retrograde Signal Regulating Presynaptic Transmitter Release , 1997, Neuron.

[2]  F. Kawasaki,et al.  A Temperature-Sensitive Paralytic Mutant Defines a Primary Synaptic Calcium Channel in Drosophila , 2000, The Journal of Neuroscience.

[3]  D. Blake,et al.  Dysbindin, a Novel Coiled-coil-containing Protein That Interacts with the Dystrobrevins in Muscle and Brain* , 2001, The Journal of Biological Chemistry.

[4]  Tao Li,et al.  The genetics of schizophrenia: glutamate not dopamine? , 2003, European journal of pharmacology.

[5]  Stephan Heckers,et al.  Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. , 2003, Pharmacology & therapeutics.

[6]  Dysbindin-1 and schizophrenia: from genetics to neuropathology. , 2004, The Journal of clinical investigation.

[7]  S. Nelson,et al.  Homeostatic plasticity in the developing nervous system , 2004, Nature Reviews Neuroscience.

[8]  Takahisa Taguchi,et al.  Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. , 2004, Human molecular genetics.

[9]  K. Kendler.  Schizophrenia genetics and dysbindin: a corner turned? , 2004, The American journal of psychiatry.

[10]  Raquel E Gur,et al.  Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. , 2004, The Journal of clinical investigation.

[11]  R. Sillitoe,et al.  Schizophrenia genetics: dysbindin under the microscope , 2004, Trends in Neurosciences.

[12]  Michael J Owen,et al.  Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia? , 2005, Schizophrenia bulletin.

[13]  C. A. Frank,et al.  Mechanisms Underlying the Rapid Induction and Sustained Expression of Synaptic Homeostasis , 2006, Neuron.

[14]  Chang-Gyu Hahn,et al.  Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. , 2006, Human molecular genetics.

[15]  M. Owen,et al.  An update on the genetics of schizophrenia , 2006, Current opinion in psychiatry.

[16]  Stephan J. Sigrist,et al.  Bruchpilot, a Protein with Homology to ELKS/CAST, Is Required for Structural Integrity and Function of Synaptic Active Zones in Drosophila , 2006, Neuron.

[17]  Sarah A. J. Reading,et al.  Neurobiology of Schizophrenia , 2006, Neuron.

[18]  R. Nazarian,et al.  Reinvestigation of the dysbindin subunit of BLOC-1 (biogenesis of lysosome-related organelles complex-1) as a dystrobrevin-binding protein. , 2006, The Biochemical journal.

[19]  L. Chen,et al.  The Drosophila cacts2 mutation reduces presynaptic Ca2+ entry and defines an important element in Cav2.1 channel inactivation , 2006, The European journal of neuroscience.

[20]  J. Coyle,et al.  Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis , 2006, Cellular and Molecular Neurobiology.

[21]  G. Davis.  Homeostatic control of neural activity: from phenomenology to molecular design. , 2006, Annual review of neuroscience.

[22]  S. Mosolov,et al.  Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial , 2007, Nature Medicine.

[23]  R. Straub,et al.  Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients , 2008, Schizophrenia Research.

[24]  Chanjuan Hao,et al.  DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release , 2008, The Journal of cell biology.

[25]  J. Meador-Woodruff,et al.  Role of glutamate in schizophrenia: integrating excitatory avenues of research , 2008, Expert review of neurotherapeutics.

[26]  T. Branco,et al.  Local Dendritic Activity Sets Release Probability at Hippocampal Synapses , 2008, Neuron.

[27]  C. A. Frank,et al.  A Presynaptic Homeostatic Signaling System Composed of the Eph Receptor, Ephexin, Cdc42, and CaV2.1 Calcium Channels , 2009, Neuron.