Striatal Magnetic Resonance Spectroscopy Abnormalities in Young Adult Sapap3 Knockout Mice

Abstract

Background Obsessive compulsive disorder (OCD) is a debilitating condition with lifetime prevalence of 1–3%. OCD typically arises in youth but delays in diagnosis impede optimal treatment and developmental studies of the disorder. Research using genetically modified rodents may provide models of etiology that enable earlier detection and intervention. The SAPAP3 knockout (KO) transgenic mouse was developed as an animal model of OCD and related disorders (OCRD). KO mice exhibit compulsive self-grooming behavior analogous to behaviors found in people with OCRD. Striatal hyperactivity has been reported in these mice and in humans with OCD. Methods Striatal and medial frontal cortex 9.4 Tesla proton spectra were acquired from young adult SAPAP3 KO and wild-type control mice to determine whether KO mice have metabolic and neurochemical abnormalities. Results Young adult KO mice had lower striatal lactate (P=0.006) and glutathione (P=0.039) levels. Among all mice, striatal lactate and glutathione levels were associated (R=0.73, P=0.007). We found no group differences in medial frontal cortex metabolites. At the age range studied, only 1 of 8 KO mice had skin lesions indicative of severe compulsive grooming. Conclusion Young adult SAPAP3 KO mice have striatal but not medial frontal cortex MRS abnormalities that may reflect striatal hypermetabolism accompanied by oxidative stress. These abnormalities typically preceded the onset of severe compulsive grooming. Our findings are consistent with striatal hypermetabolism in OCD. Together, these results suggest that striatal MRS measures of lactate or glutathione might be useful biomarkers for early detection of risk for developing compulsive behavior disorders.

Lower Posterior Cingulate Cortex Glutathione Levels in Obsessive-Compulsive Disorder

“…These additional findings suggest that peripheral oxidative stress in people with OCD could be associated with, or related to, central abnormalities. Our present human findings are also consistent with our report of concurrent striatal GSH depletion and metabolic stress in the Sapap3 knockout mouse model of OCRD (34). Future studies examining both brain GSH and peripheral markers of oxidative stress in people with OCD and other OCRD would help to further elucidate the relationship between central and peripheral oxidative stress in people with these disorders.…”

“…As noted above, this study also acquired data in the PCC as a comparison region, but we decided not to examine these data in our primary analysis, due to the large amount of data to be analyzed and reported. However, after we published the results of this primary analysis, a study in our center found decreased striatal GSH levels in the Sapap3 knockout mouse model of OCRD (34). Accordingly, we returned to analyze our PCC data with a specific a priori hypothesis of lower GSH levels in the OCD group.…”

“…Given evidence that individuals with OCD display PCC hyperactivation or hypermetabolism, both at rest (31) and during cognitive challenge paradigms (28, 29), which is attenuated by selective serotonin reuptake inhibitors (SSRIs) (31), and which predicts clinical response to SSRIs (32) and anterior cingulotomy (33), we hypothesized that individuals with OCD would have lower GSH levels in PCC than non-OCD comparison individuals. This hypothesis was further stimulated by a recent finding in our center that striatal GSH levels are decreased in the Sapap3 knockout mouse model of OCRD (34). To test this hypothesis, we compared PCC GSH/total creatine (Cr) ratios in individuals with OCD versus those without OCD.…”

Oxidative and nitrosative stress markers in obsessive–compulsive disorder: a systematic review and meta‐analysis

“…Furthermore, OCD patients were found to have a higher frequency of neuronal nitric oxide synthase ( NOS1) rs 2682826 C allele (276C>T) . Evidence from studies in transgenic mouse models of OCD and related disorders have also supported the possibility that such genetic variations predispose to an increased vulnerability to oxidative stress, with mice lacking the glutamate transporter SCL1A1 (strongly expressed in the CSTC circuit) showing increased vulnerability to oxidants and reduced capacity to metabolize ROS , and SAPAP3 knockout transgenic mice showing lower lactate and glutathione levels in the striatum prior to the establishment of compulsive self‐grooming behavior .…”

Simultaneous detection of glutathione and lactate using spectral editing at 3 T

“…Lactate (Lac) is an indicator of non‐oxidative glycolysis, the elevation of which is considered as an indicator of metabolic abnormalities or oxygen deficiency . Both metabolites can be detected non‐invasively by in viv o 1 H magnetic resonance spectroscopy (MRS), and have been implicated in the pathophysiology of various brain pathologies, such as schizophrenia, bipolar disorder, obsessive–compulsive disorder and chronic fatigue syndrome . The detection of either metabolite using MRS, however, is not trivial because of their relatively low in vivo concentrations under normal conditions.…”