Abstract
BackgroundThe anterior cingulate cortex (ACC) is a brain area involved in modulating behavior associated with social interaction, disruption of which is a core feature of autism spectrum disorder (ASD). Functional brain imaging studies demonstrate abnormalities of the ACC in ASD as compared to typically developing control patients. However, little is known regarding the cellular basis of these functional deficits in ASD. Pyramidal neurons in the ACC are excitatory glutamatergic neurons and key cellular mediators of the neural output of the ACC. This study was designed to investigate the potential role of ACC pyramidal neurons in ASD brain pathology.MethodsPostmortem ACC tissue from carefully matched ASD and typically developing control donors was obtained from two national brain collections. Pyramidal neurons and surrounding astrocytes were separately collected from layer III of the ACC by laser capture microdissection. Isolated RNA was subjected to reverse transcription and endpoint PCR to determine gene expression levels for 16 synaptic genes relevant to glutamatergic neurotransmission. Cells were also collected from the prefrontal cortex (Brodmann area 10) to examine those genes demonstrating differences in expression in the ACC comparing typically developing and ASD donors.ResultsThe level of NTRK2 expression was robustly and significantly lower in pyramidal neurons from ASD donors as compared to typically developing donors. Levels of expression of GRIN1, GRM8, SLC1A1, and GRIP1 were modestly lower in pyramidal neurons from ASD donors, but statistical significance for these latter genes did not survive correction for multiple comparisons. No significant expression differences of any genes were found in astrocytes laser captured from the same neocortical area. In addition, expression levels of NTRK2 and other synaptic genes were normal in pyramidal neurons laser captured from the prefrontal cortex.ConclusionsThese studies demonstrate a unique pathology of neocortical pyramidal neurons of the ACC in ASD. NTRK2 encodes the tropomyosin receptor kinase B (TrkB), transmission through which neurotrophic factors modify differentiation, plasticity, and synaptic transmission. Reduced pyramidal neuron NTRK2 expression in the ACC could thereby contribute to abnormal neuronal activity and disrupt social behavior mediated by this brain region.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-015-0023-2) contains supplementary material, which is available to authorized users.
Highlights
The anterior cingulate cortex (ACC) is a brain area involved in modulating behavior associated with social interaction, disruption of which is a core feature of autism spectrum disorder (ASD)
The findings of this study demonstrate that ACC in ASD is associated with abnormal levels of expression of several genes related to glutamate neurotransmission, with the most striking finding being a robust reduction of NTRK2 gene expression
Levels of GRM8 expression were modestly lower in pyramidal neurons from ASD donors compared to matched control donors (t = 2.89; P = 0.034), but statistical significance was lost when the P value was corrected for the number of matched pair comparisons of gene expressions in neurons (Table 2)
Summary
The anterior cingulate cortex (ACC) is a brain area involved in modulating behavior associated with social interaction, disruption of which is a core feature of autism spectrum disorder (ASD). Functional brain imaging studies demonstrate abnormalities of the ACC in ASD as compared to typically developing control patients. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes repetitive behaviors and impairments in social communication and interaction [1]. Functional MRI studies have demonstrated differences when comparing typically developed controls with ASD patients, including reduced activation of the anterior cingulate cortex (ACC) during true/false judgments [4], novelty detection [5], response inhibition [6,7], attention tasks [8], and increased activation of the ACC during social target detection and nonsocial rewarding [9]. Other studies using SPECT [10], EEG [11,12,13,14], PET [15,16,17,18], and fractional anisotropy [19,20] have demonstrated abnormalities in the cingulate cortex in ASD
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