A GABAergic cortical deficit dominates schizophrenia pathophysiology

E. Costa, J. M. Davis, E. Dong, D. R. Grayson, A. Guidotti, L. Tremolizzo, Marin D Veldic

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Several lines of evidence support the role of an epigenetic-induced GABAergic cortical dysfunction in schizophrenia psychopathology, which is probably dependent on an increase in the expression of DNA-methyltransferase-1 occurring selectively in GABAergic neurons. The key enzyme regulating GABA synthesis, termed glutamic acid decarboxylase 67 (GAD67) and the important neurodevelopmental protein called reelin are coexpressed in GABAergic neurons. Upon release, GABA and reelin bind to postsynaptic receptors located in dendrites, somata, or the axon initial segment of pyramidal neurons. Because GAD67 and reelin are downregulated in schizophrenia, it is suggested that schizophrenics may express GABAergic deficit-related alterations of pyramidal neuron function. A reduction of dendritic spines is a finding reported in the prefrontal cortex of schizophrenia patients. Because dendritic spines are innervated by glutamatergic axon terminals, very probably this reduction of dendritic spine expression is translated into a functional deficit of glutamatergic transmission. Plastic modifications of neuronal circuits are probably dependent on GABAergic transmitter tone, and it is likely that GABAergic dysfunction is at the root of synaptic plasticity deficits in schizophrenia. Thus, a possible avenue for the treatment of schizophrenia would be to address this GABAergic functional deficit using positive allosteric modulators of the action of GABA at GABAA receptors. Benzodiazepines (BZ) such as diazepam are effective in treating positive and negative symptoms of schizophrenia, but because they positively modulate GABAA receptors expressing (α1 subunits, these BZs cause sedation and tolerance. In contrast, imidazenil, a full allosteric modulator of GABA A receptors expressing α5 subunits may reduce psychotic symptomatology without producing sedation. Hence, imidazenil should be appropriately studied as a prospective candidate for a pharmacological intervention in schizophrenia.

Original languageEnglish (US)
Pages (from-to)1-23
Number of pages23
JournalCritical Reviews in Neurobiology
Volume16
Issue number1-2
StatePublished - 2004
Externally publishedYes

Fingerprint

Schizophrenia
Dendritic Spines
GABA-A Receptors
GABAergic Neurons
Glutamate Decarboxylase
Pyramidal Cells
gamma-Aminobutyric Acid
GABA Modulators
Neuronal Plasticity
Presynaptic Terminals
Methyltransferases
Carisoprodol
Diazepam
Dendrites
Prefrontal Cortex
Psychopathology
Benzodiazepines
Epigenomics
Plastics
Down-Regulation

Keywords

  • Benzodiazepines
  • Dendritic spines
  • DNA-methyltransferase 1
  • Epigenetic
  • GABA
  • GABAergic neurons
  • Glutamate
  • Glutamatergic neurons
  • Imidazenil
  • Phencyclidine
  • Reelin
  • Schizophrenia

ASJC Scopus subject areas

  • Clinical Neurology
  • Physiology
  • Neuroscience(all)

Cite this

Costa, E., Davis, J. M., Dong, E., Grayson, D. R., Guidotti, A., Tremolizzo, L., & Veldic, M. D. (2004). A GABAergic cortical deficit dominates schizophrenia pathophysiology. Critical Reviews in Neurobiology, 16(1-2), 1-23.

A GABAergic cortical deficit dominates schizophrenia pathophysiology. / Costa, E.; Davis, J. M.; Dong, E.; Grayson, D. R.; Guidotti, A.; Tremolizzo, L.; Veldic, Marin D.

In: Critical Reviews in Neurobiology, Vol. 16, No. 1-2, 2004, p. 1-23.

Research output: Contribution to journalArticle

Costa, E, Davis, JM, Dong, E, Grayson, DR, Guidotti, A, Tremolizzo, L & Veldic, MD 2004, 'A GABAergic cortical deficit dominates schizophrenia pathophysiology', Critical Reviews in Neurobiology, vol. 16, no. 1-2, pp. 1-23.
Costa E, Davis JM, Dong E, Grayson DR, Guidotti A, Tremolizzo L et al. A GABAergic cortical deficit dominates schizophrenia pathophysiology. Critical Reviews in Neurobiology. 2004;16(1-2):1-23.
Costa, E. ; Davis, J. M. ; Dong, E. ; Grayson, D. R. ; Guidotti, A. ; Tremolizzo, L. ; Veldic, Marin D. / A GABAergic cortical deficit dominates schizophrenia pathophysiology. In: Critical Reviews in Neurobiology. 2004 ; Vol. 16, No. 1-2. pp. 1-23.
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