Dendritic spine hypoplasticity and downregulation of reelin and GABAergic tone in schizophrenia vulnerability.
In this review, we will first present a brief overview of the current understanding of: (a) the biology of reelin; (b) the putative reelin signaling pathways via integrin receptor stimulation; (c) the cytosolic adapter protein DAB1, which appears to be operative in the transduction of reelin's pleiotropic actions in embryonic, adolescent, and adult brain; (d) the regulation of GABAergic function, including some aspects of GABAergic system development; and (e) dendritic spine function and its role in the regulation of synaptic plasticity. We argue that a downregulation of reelin expression occurring in prefrontal cortex and in every brain structure of schizophrenia patients so far studied may be associated with a decrease in dendritic spine expression that in turn may provide an important reduction of cortical function as documented by the downregulation of glutamic acid decarboxylase67 (GAD67) expression, which might be secondary to a reduction of GABAergic axon terminals. This hypothesis is supported by a genetic mouse model of reelin haploinsufficiency that replicates the above-described dendritic and presynaptic GABAergic defects documented in schizophrenia brains.
Costa
E
E
Psychiatric Institute, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Davis
J
J
Grayson
D R
DR
Guidotti
A
A
Pappas
G D
GD
Pesold
C
C
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001714:Bipolar Disorder / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002452:Cell Count; D002465:Cell Movement; D002648:Child; D003712:Dendrites / Q000648:ultrastructure*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000096:biosynthesis / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D039422:Integrin alpha3; D016023:Integrins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D001523:Mental Disorders / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008959:Models, Neurological; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity; D009474:Neurons / Q000145:classification / Q000378:metabolism / Q000648:ultrastructure; D017397:Prefrontal Cortex / Q000196:embryology / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D000091042:Reelin Protein; D012559:Schizophrenia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012697:Serine Endopeptidases; D015398:Signal Transduction / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D015703:Antigens, CD; D015816:Cell Adhesion Molecules, Neuronal; C113062:DAB1 protein, Neurospora crassa; D016326:Extracellular Matrix Proteins; D005656:Fungal Proteins; D039422:Integrin alpha3; D016023:Integrins; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D005680:gamma-Aminobutyric Acid; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1