Glutamate homeostasis in the adult rat prefrontal cortex is altered by cortical docosahexaenoic acid accrual during adolescence: An in vivo1H MRS study

Abstract

Major psychiatric disorders are associated with dysregulated glutamate homeostasis and deficits in the omega-3 fatty acid docosahexaenoic acid (DHA). This study determined the effects of dietary-induced alterations in brain DHA accrual on cortical glutamate homeostasis in the adult rat brain. Adolescent rats were fed a control diet (n = 20), a n-3 fatty acid-deficient diet (DEF, n = 20), or a fish oil-fortified diet containing preformed DHA (FO, n = 20). In adulthood ¹H MRS scans were performed with voxels in the prefrontal cortex (PFC) and thalamus. Compared with controls, erythrocyte, PFC, and thalamus DHA levels were significantly lower in DEF rats and significantly higher in FO rats. In the PFC, but not the thalamus, glutamate was significantly elevated in DEF rats compared with controls and FO rats. Glutamine did not differ between groups and the glutamine/glutamate ratio was lower in DEF rats. No differences were observed for markers of excitotoxicity (NAA, GFAP), or astrocyte glutamate transporter (GLAST, GLT-1) or glutamine synthetase expression. Across diet groups, PFC DHA levels were inversely correlated with PFC glutamate levels and positively correlated with GLAST expression. Together these findings demonstrate that rat cortical DHA accrual during adolescence impacts glutamate homeostasis in the adult PFC.

Keywords: Docosahexaenoic acid (DHA); Glutamate; Glutamate transporter; Glutamine synthetase; Omega-3 fatty acids; Rat.

Figure 1

The 7T Bruker Biospec Imaging System (A), a ¹H MRS spectrum from a control mPFC (B), voxel placement in mPFC in the sagittal (C) and coronal (D) orientations, and voxel placement in thalamus in the sagittal (E) and coronal (F) orientations. Cr, creatine; Glx, glutamate+glutamine; mI, myo-inositol; Tau, protein; Cho, choline; NAA, N-acetyl aspartate; NAAG, N-acetyl aspartylglutamate; Gln, glutamine; Glu, glutamate.

Figure 2

Erythrocyte (A), PFC (B), and thalamus (C) DHA composition in adult rats maintained on the control diet (CON), n-3-free diet (DEF), and fish oil-fortified diet (FO)(n=20/group) during peri-adolescent development. Values are group mean composition (mg fatty acid/100 mg fatty acids) ± S.E.M. *P≤0.05, ***P≤0.0001 vs. CON, ^###P≤0.0001 vs. FO.

Figure 3

Concentrations of glutamate (Glu), glutamine (Gln), and the Gln/Glu ratio in the PFC (A,B,C) and thalamus (D,E,F) of adult rats maintained on the control diet (CON), n-3-free diet (DEF), and fish oil-fortified diet (FO) during peri-adolescent development. Values are group mean institutional units (IU) ± S.E.M. (n=20/group). *P≤0.05 vs. CON, ^#P≤0.01, ^##P≤0.001 vs. FO.

Figure 4

Expression of astrocyte glutamate-aspartate transporter (GLAST)(A), glial-specific glutamate transporter-1 (GLT-1)(B), glutamine synthetase (GS)(C), and glial fibrillary acidic protein (GFAP)(D) in the PFC of adult rats maintained on the control diet (CON), n-3-free diet (DEF), and fish oil-fortified diet (FO) during peri-adolescent development. Values are group mean ΔC_T ± S.E.M. (n=16–18/group).

Figure 5

Relationships between PFC DHA and glutamate levels (A), PFC DHA and GLAST mRNA expression levels (B), and PFC glutamate and GLAST mRNA expression levels. Pearson correlation coefficients and associated p-values (two-tailed) are presented.