Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

Abstract

Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytrypatmine 2A receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-D-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved. Dopamine and serotonin, as opposed to emerging interest in glutamate, played a dominant role during the formative years of modern psychopharmacology when thinking about the pathophysiology and treatment of schizophrenia. Models derived from studying the behavioral effects of amphetamine and serotonergic hallucinogens were emphasized (Table 1). The seminal observations by Arvid Carlsson and his colleagues in the late early 1960s that first postulated functional dopamine receptor blockade as a necessary therapeutic action by the phenothiazine and butyrophenone structural classes set the stage for our current mechanistic understanding of all antipsychotic drugs currently used today (Carlsson and Lindqvist, 1963). The emergence of in vitro receptor binding and positron emission topography receptor occupancy studies in healthy volunteers and patients identified dopamine D2 receptor Article, publication date, and citation information can be found at

Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment

“…Although the major theories relate to a hypofunction of the NMDA receptor (NMDAR) (Marek et al, 2010), metabotropic glutamate receptors (mGluR) have also been implicated (Niswender and Conn, 2010). Metabotropic glutamate receptor 5 (mGluR5) is one of eight known glutamate-specific G-protein coupled receptors which has been shown to uniquely modulate NMDAR activity through a physical and functional link (Tu et al, 1999;Alagarsamy et al, 2002;Luccini et al, 2007).…”

Análise proteômica da esquizofrenia

“…Consistent differences across the different brain regions analyzed were also observed in energy metabolism-related proteins supporting the "hypofrontality" concept, and reduced blood flow in some regions of the brain [12][13][14] . The consistent differential expression of ALDOC, ENO2, HK1, PGAM1, TPI1 and GAPDH place Glycolysis as one of the main biochemical pathway for further studies, basic or clinical.…”

“…Prior to LC-MS/MS, protein or peptide of each sample are labeled with two to four stable isotopes -so called tags. The tags are chemically identical, but may carry different combination of heavy isotopes, usually 2 H, 13 C or 15 N. Since the mass of the tags are known, it is possible to identify by MS labeled peptides, allowing the identification of peptides. The relative quantification is performed by comparing the peak intensities of each peptide labeled with different tags.…”

The Unique Properties of the Prefrontal Cortex and Mental Illness

“…A remarkable number of genetic insults in schizophrenia involve proteins found at prefrontal synapses. There are well-established genetic changes associated with NMDA receptor signaling [160][161][162], DA [51,[163][164][165], GABA [112,116,140,166], and α7 nicotinic receptors [167][168][169][170]. More recently, a number of high-risk genes are found to be associated with schizophrenia [171].…”