Die Glutamathypothese der Schizophrenie

Abstract

For many years, the dopamine hypothesis of schizophrenia has been the leading theory explaining the aetiology of schizophrenia. However, since the first observation showed that NMDA-receptor antagonists (e. g., PCP) can induce all kinds of schizophrenia symptoms in humans, the glutamate hypothesis of schizophrenia has been established as an additional explanation model. Apart from the PCP-induced psychoses, many other findings from all areas of modern neuroscience have confirmed and extended the glutamate hypothesis. This review discusses the available evidence for the glutamate hypothesis and puts the different findings into relation. Consecutively, the possibilities for a pharmacological modulation of the glutamate system and recent clinical trials are discussed. To sum up, one could note that the glutamate hypothesis of schizophrenia is now well-established. The development of glutamatergic antipsychotics is still in the early stages, but there is hope for a new generation of antipsychotics based on the glutamate hypothesis of schizophrenia. However, recent findings from registration trials could not provide positive findings for the recently developed glutamatergic drugs.

Glial loss of the metallo β-lactamase domain containing protein, SWIP-10, induces age- and glutamate-signaling dependent, dopamine neuron degeneration

“…At neuronal synapses, Glu signals through both metabotropic receptors that initiate G-protein coupled signaling [ 5 – 7 ] as well as ionotropic receptors that flux ions such as Na + and Ca 2+ , altering membrane excitability [ 5 , 8 – 10 ]. Excessive ionotropic Glu signaling in the mammalian brain has been implicated in a variety of brain disorders including addiction, schizophrenia, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD) [ 11 – 14 ], as well as the neuronal death that arises in the context of stroke and glioblastoma [ 15 , 16 ]. Acute treatment of neurons with high, non-physiological, levels of Glu can induce signs of cell death within minutes, characterized by intense vacuolization and cell swelling characteristic of necrosis [ 17 – 20 ].…”

Risikofaktoren für die Entstehung und den Verlauf der Schizophrenie

“…Der Theorie der regionalen Spezifität folgend, scheint es sich um eine dopaminerge Hyperaktivität im mesolimbischen System sowie eine Unterfunktion frontokortikaler Strukturen und deren interkonnektierenden Arealen zu handeln (Hypofrontalität). Wobei die mesolimbische Überfunktion eher mit Positivsymptomen verbunden zu sein scheint und die Negativsymptomatik eher der Hypofrontalität zugeschrieben wird 10 .…”

TMS-EEG signatures of glutamatergic neurotransmission in the human cortex

“…Drugs acting on the excitatory glutamatergic system have so far not been tested with TMS-EEG measures, although glutamatergic neurotransmission plays a fundamental role in the excitation-inhibition balance to regulate neuronal excitability in cerebral cortex 18 . Moreover, the pathophysiology of many neurological and psychiatric conditions is linked to a dysfunction in the glutamatergic system, such as schizophrenia 19 , epilepsy 20 or amyotrophic lateral sclerosis 21 .…”