Markers of glutamate synaptic transmission and plasticity are increased in the anterior cingulate cortex in bipolar disorder

Abstract

Background: Cortical glutamate levels are elevated in bipolar disorder, but the interpretation of this increase is unclear because glutamate has metabolic as well as neurotransmitter roles. We investigated this by measuring vesicular glutamate transporter 1 (VGluT1) expression, which reflects activity at glutamate synapses. We also measured netrin-G1 and netrin-G2 messenger RNAs because these genes are involved in the formation and plasticity of glutamatergic connections.

Methods: Using quantitative polymerase chain reaction, we quantified transcripts for VGluT1, netrin-G1 (isoforms G1c, G1d, and G1f), and netrin-G2 in the anterior cingulate cortex from subjects with bipolar disorder (n = 34), schizophrenia (n = 35), and healthy control subjects (n = 35).

Results: Vesicular glutamate transporter 1, netrin-G2, and netrin-G1d and G1f were increased in bipolar disorder but not in schizophrenia. Netrin-G1c did not differ between groups. Netrin-G1c and netrin-G1f expression showed left-right asymmetries. Vesicular glutamate transporter 1 messenger RNA correlated with brain weight.

Conclusions: Increased VGluT1 expression is supportive of elevated glutamate neurotransmission in the anterior cingulate cortex in bipolar disorder. The netrin-G1 and netrin-G2 findings suggest there may be an underlying difference in the plasticity of the affected circuitry.

Figure 1

VGluT1 mRNA abundance correlates with (A) fresh brain weight and (B) freezer storage time. C: VGluT1 mRNA increased in bipolar disorder (BIP, squares) but not schizophrenia (SCZ, inverted triangles) compared to controls (CON, triangles). See Table 2 and text for analyses.

Figure 2

Expression of netrin-G1 and –G2 mRNAs in ACC in bipolar disorder and schizophrenia using qPCR. All data shown are normalised to the geometric mean of the four housekeeping transcripts. A: Netrin-G2 mRNA is increased in bipolar disorder but not schizophrenia. B: Netrin-G1c mRNA shows no diagnostic differences, but has higher expression in the left ACC compared to the right ACC. C: Netrin-G1d mRNA is increased in bipolar disorder but not schizophrenia. D: Netrin-G1f mRNA shows a normal left>right asymmetry, and a right-lateralised increase in bipolar disorder. Symbols as in Fig. 1.

Figure 3

A: Distribution of netrin-G2 mRNA in human ACC, showing concentration in deep laminae (V/VI) compared to superficial laminae (II/III) and to white matter (wm). B: Distribution of netrin-G1 mRNA in human ACC, showing a lower signal, but with relative enhancement in superficial laminae (II/III).