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.

Keywords: Magnetic resonance spectroscopy; Obsessive compulsive disorder; Oxidative stress; SAPAP3 protein; Striatal dysfunction; Translational model.

Figure 1

Age distributions of wild type control (WT) and SAPAP3 knockout (KO) mice in this study stratified by genotype and MRS brain area: left striatum (Str) or medial frontal cortex (MFC). Mean ages are shown for each group as horizontal lines. The arrow identifies the mouse with skin lesions, indicative of the severe compulsive grooming phenotype.

Figure 2

Representative left striatal (Panel a) and medial frontal cortex (Panel b) spectra and LCmodel fits and residual fits from wild-type control mice. LCmodel fits for striatal lactate and glutathione are shown separately (Panel a). Insets illustrate positions of a left striatal MRS voxel (Panel a) and a medial frontal cortex voxel (Panel b) superimposed onto coronal brain slices. The following metabolites are identified: Choline: Cho; Creatine: Cr, GABA; Glutamate: Glu; Glutamine: Gln; Glutamate/glutamine: Glx; Glutathione: GSH; myo-inositol (Ins); Lactate: Lac; N-acetylaspartate: NAA; Phosphocreatine: PCr; Taurine: Tau.

Figure 3

Correlation plot showing the relationship between striatal water normalized lactate and glutathione levels (including only measurements with Cramér-Rao Lower Bound (CRLB) values ≤ 30%). Wild type mice (WT, N=7, 1 mouse had a lactate CRLB <30%) are shown as open circles and SAPAP3 knockout mice (KO, N=5, 3 mice had lactate CRLBs <30%) are shown as filled circles. Also shown is the 95% confidence interval.