Glutamatergic hypothesis of schizophrenia: involvement of Na+/K+-dependent glutamate transport

Abstract

Hypothetical model based on deficient glutamatergic neurotransmission caused by hyperactive glutamate transport in astrocytes surrounding excitatory synapses in the prefrontal cortex is examined in relation to the aetiology of schizophrenia. The model is consistent with actions of neuroleptics, such as clozapine, in animal experiments and it is strongly supported by recent findings of increased expression of glutamate transporter GLT in prefrontal cortex of patients with schizophrenia. It is proposed that mechanisms regulating glutamate transport be investigated as potential targets for novel classes of neuroactive compounds with neuroleptic characteristics. Development of new efficient techniques designed specifically for the purpose of studying rapid activity-dependent translocation of glutamate transporters and associated molecules such as Na+, K+-ATPase is essential and should be encouraged.

Deletion of Adenosine A2A Receptors From Astrocytes Disrupts Glutamate Homeostasis Leading to Psychomotor and Cognitive Impairment: Relevance to Schizophrenia

“…Finally, GLT-I overexpression exacerbates deficits on PPI of the startle response induced by phencyclidine (19). Therefore, although not without its share of disagreement (58), there are a fair amount of data linking GLT-I dysfunction to schizophrenia (59). The identification of astrocytic A 2A R as a critical trigger and astrocytic GLT-I as primary downstream target underlying motor and memory dysfunctions illustrates the critical role that astrocytes may operate in the development of some of the brain modifications observed in schizophrenia (7).…”

DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in schizophrenic patients – support for the glutamate hypothesis of schizophrenias

“…The glutamatergic neurotransmitter system has frequently been suggested to be involved in the pathophysiology of schizophrenias (Goff & Coyle 2001; Kim et al 1980; Moghaddam & Krystal 2003; Nanitsos et al 2005). On the assumption of a deficient glutamatergic neurotransmission in patients with schizophrenia (Laruelle et al 2005), a differential impact of genes coding for proteins that are involved in the glutamate system (e.g.…”

Inhibitors of glutamate transport modulate distinct patterns in brain metabolism

“…The EAAT‐specific metabolic sequelae may also give some clue as to the local receptor environments of these transporters. As alterations in GluT have been linked to a variety of pathologic conditions (Maragakis and Rothstein,2004; Matute et al,2005; Nanitsos et al,2005) as well as mechanisms of centrally acting drugs (Melone et al,2001; Hinoi et al,2005), the present observations should be of interest whenever etiologies and treatment of mental disorders are discussed.…”