Based on the pivotal role of glutamate in CSTC models of OCD, Rosenberg and Keshavan (1998)
reasoned that glutamate dysfunction might be implicated in the pathogenesis of OCD. Their hypothesis was based on the integral role of glutamate as the key neurotransmitter within CSTC circuits. One of the leading models of OCD is based on the balance between direct and indirect pathways within CSTC circuits (Saxena et al., 2001
). According to this theory, reciprocal interaction between direct (ultimately leads to thalamic stimulation of cortex) and indirect (ultimately leads to thalamic inhibition of cortex) normally resulted in a dynamic balance with no one pathway predominating. Hyperactivity of the direct pathway, or hypoactivity of the indirect pathway was thought to lead to disinhibition of CSTC circuits and consequent release of hardwired behaviours (compulsions) and cognitions (obsessions) that were normally held in check. Rosenberg and others at the time (also see Carlsson, 2001
) reasoned that over-activity of the direct pathway and associated hyperactivity of glutamate (the major excitatory neurotransmitter in this pathway) could lead to the development of OCD.
Further indirect support for the role of glutamate dysfunction in OCD was also provided by the DICT-7 mouse model, which amounted to a test of the CSTC hypothesis in mice, since it was based on engineering transgenic mice in which glutamatergic neurons in the direct pathway (which express D1) were chronically hyperstimulated. In DICT-mice OCD- and tic-like behaviour were observed to be associated with stimulation of direct CSTC circuits; furthermore, as noted above this behaviour was exacerbated by NMDA antagonists (Campbell et al., 1999
; McGrath 2000
). The group investigating the DICT-7 mice outlined a “cortical-limbic glutamatergic neuron (CGN)” hyperactivity model of tic and OCD symptoms, which elaborated on earlier CSTC models of OCD and attempted to account for the role of glutamate, dopamine and serotonin within direct and indirect CSTC pathways (Nordstrom and Burton, 2002
While the DICT-7 model was being developed, more direct evidence for glutamatergic dysfunction in OCD was being gathered by Rosenberg and colleagues in their series of MRS studies described above (Rosenberg et al., 2000
). Their findings were consistent with their earlier predictions, and led them to propose that they had identified a reversible (with treatment), glutamatergically mediated thalamo-cortical-striatal dysfunction in OCD (Rosenberg, 2001
). Their initial findings of increased Glx in caudate taken together with findings of elevated glutamate of CSF in patients with OCD (Chakrabarty et al., 2005
), seemed consistent with the CGN model of general glutamatergic hyperactivity in OCD within CSTC circuits. However, importantly Rosenberg and others found that Glx concentrations were not uniformly activated but showed regional specificity. Based on these findings, Rosenberg and colleagues (2004)
hypothesized that OCD was associated with tonic-phasic dysregulation of glutamate within CSTC circuits, including reduced tonic glutamate levels in ACC (as evidenced by decreased Glx) which in turn led to phasic overactivity in the striatum and orbitofrontal cortex (as evidenced by increased Glx in both regions) (Rosenberg et al., 2004
Although there has been accumulating evidence for glutamatergic dysfunction in OCD, until recently there were no studies that could help elucidate the nature of this dysfunction. As pointed out by Pittenger and colleagues (2006)
, there could be many possible causes for the altered glutamate levels seen in MRS studies, including presynaptic and/or post-synaptic neuronal mechanisms and/or altered glial functioning. However, there is now evidence from both candidate gene studies and animal models which suggest that post-synaptic dysfunction in glutamate signalling represents the most likely candidate mechanism at the molecular level to explain the higher order changes seen in CSTC glutamate transmission (for a recent review discussing this hypothesis see Ting and Feng, 2008
). First, the most replicated gene finding in OCD is an association with SLC1A1
, which encodes the EAAT3/EAAC1 glutamate transporter predominantly expressed on the post-synaptic and peri-synaptic membrane. Another candidate gene with some evidence for association, GRIN2B
encodes the NMDA-2B subunit which is expressed predominantly in the same cellular location and interacts with SLC1A1
(Scimemi et al., 2009
). Second, the two animal knockout models of DLGAP3
indicate that changes in genes involved in post-synaptic scaffolding and glutamate signalling can produce remarkably similar compulsive behaviours. Furthermore, both mouse models yielded direct evidence of altered glutamate receptor expression and electrophysiological changes known to reflect glutamate signalling. Finally, the emerging findings in OCD are consistent with the mounting evidence in autistic spectrum disorders of glutamatergic post-synaptic dysfunction (Van Spronsen et al., 2010
). This overlap in putative mechanisms is intriguing given the known phenotypic overlap in these disorders characterized by repetitive behaviours.
In this era of evidence based medicine it can take years to translate basic science discoveries to clinical practice. However, in the case of the glutamate hypothesis, the translation of research findings to development of novel therapeutic strategies has been quite rapid. The first case-control MRS study identifying glutamatergic dysfunction in OCD was reported by Rosenberg and colleagues (2000)
. Since that time, we have seen converging evidence from animal models, genetic studies, and most recently imaging genetic studies provide the rationale for novel treatment development trials. To date, riluzole and memantine are under active study. Memantine has already shown promise in a small randomized trial, whereas riluzole is being investigated in a randomized, double-blind placebo-controlled trial at the NIMH. Both medications are being used regularly in clinics in North America and other glutamatergic compounds are being studied. The translation of findings from “bench” to “bedside” in this case has therefore taken between 5 and 10 years. This remarkably rapid progress provides an excellent example of translational research in which neuroimaging, genetics and treatment studies all have the potential to inform one another and lead to accelerating discovery of novel medications and improved understanding of pathogenesis.