A Role for Glutamate Receptors, Transporters, and Interacting Proteins in Cortical Dysfunction in Schizophrenia

While there are myriad genetic, environmental, and epigenetic risk factors for schizophrenia, there is broad consensus that abnormal glutamate neurotransmission has a role in the ultimate clinical manifestations of this devastating illness. The glutamate hypothesis has evolved beyond the simplistic notion of NMDA receptor dysfunction, based in part on the dearth of consistently reproducible findings for altered NMDA receptor and binding site expression in postmortem studies. In this review, we review cortical glutamate receptor expression in this illness, and highlight postmortem data from novel families of glutamate receptor interacting proteins. We also discuss the vesicular and plasma membrane glutamate transporters, and review studies that have examined cortical glutamate transporter expression in this illness. Finally, we discuss the hypothesis that trafficking, assembly of signaling complexes, and receptor recycling might be dysregulated and represent important new targets for pharmacological manipulation in the treatment of schizophrenia. 6.1 Cortical Dysfunction in Schizophrenia Converging lines of evidence implicate cortical dysfunction in schizophrenia (reviewed in Manoach 2003; Tamminga et al. 1992; Quintana et al. 2004; Liu et al 2006; Utsunomiya-Tate et al. 1996; Lehre et al. 1995; Hisano 2003; Varoqui et al. 2002). Cognitive deficits and other negative symptoms of schizophrenia are postulated to be the result of abnormalities in frontal and temporal cortices. Abnormalities of working memory, executive function, facial recognition and other cortical functions attributed to these regions have been found by a growing number of functional neuroimaging studies in this illness (Andreasen et al. 1998; Weinberger et al. 2001; Manoach 2003). Normal cortical function relies, in part, on carefully balanced glutamatergic (excitatory) and GABAergic (inhibitory) circuitry, strengthening or weakening of individual synapses, and modulatory input from myriad neurotransmitters and paracrine factors. Since these molecular mechanisms underlie normal cortical activity, they are high yield targets for investigation of cortical abnormalities in schizophrenia. In this review, we focus on one element of cortical pathophysiology in schizophrenia: postmortem studies that support the hypothesis of abnormal cortical glutamatergic neurotransmission in this illness. 6.2 Glutamate in Schizophrenia For decades, schizophrenia research has focused on the dopamine hypothesis of schizophrenia, which postulates that dysregulated dopaminergic neurotransmission is a key feature of the pathophysiology of the illness. The dopamine hypothesis is based on the observation that antipsychotic efficacy for positive symptoms is associated with D2 dopamine receptor blockade. Although numerous studies point to dopaminergic abnormalities in schizophrenia, dopamine dysfunction does not completely account for all of the symptoms seen in schizophrenia, since antipsychotics typically are effective only for the positive symptoms of the illness, while negative symptoms and cognitive deficits are relatively refractory to treatment (Joyce and Meador-Woodruff 1997; Laruelle et al. 1999). Consequently, alternative neurotransmitter systems that may also be involved in the pathophysiology of schizophrenia have been sought, and a growing body of evidence now implicates glutamatergic dysfunction in this illness. The strongest evidence is that phencyclidine (PCP) and similar compounds, which are uncompetitive antagonists of the NMDA receptor, can induce both the positive and negative symptoms of schizophrenia, including cognitive deficits (Javitt and Zukin 1991; Tamminga 1999). Moreover, these compounds can exacerbate both positive and negative symptoms in schizophrenia (Lahti et al. 1995). Chronic administration of PCP-like compounds reduces frontal lobe blood flow and glucose utilization, which is similar to the “hypofrontality” described in schizophrenia (Hertzmann et al. 1990). More specifically, the most widely held hypotheses posit diminished NMDA receptor function in limbic brain structures, including the prefrontal cortex. There is compelling evidence for altered glutamatergic neurotransmission in the cortex in schizophrenia. 6.3 Glutamate Neurotransmission The release, activity as a ligand, and reclamation of glutamate involves three distinct cell types: the astrocyte, presynaptic neuron and postsynaptic neuron (Salt and Eaton 1996). In the presynaptic neuron, glutamine can be converted to glutamate by the enzyme glutaminase, and packaged into vesicles by a family of vesicular glutamate transporters (VGLUT1-3) for release into the synapse (Bellocchio et al. 2000; Takamori et al. 2000). Glutamate may also be synthesized by the hydrolysis of N-acetyl-alpha-L-aspartyl-L-glutamate (NAAG) into NAA 114 Deborah Bauer et al.