Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations

Abstract

Dementia with Lewy bodies (DLB) patients frequently experience well formed recurrent complex visual hallucinations (RCVH). This is associated with reduced blood flow or hypometabolism on imaging of the primary visual cortex. To understand these associations in DLB we used pathological and biochemical analysis of the primary visual cortex to identify changes that could underpin RCVH. Alpha-synuclein or neurofibrillary tangle pathology in primary visual cortex was essentially absent. Neurone density or volume within the primary visual cortex in DLB was also unchanged using unbiased stereology. Microarray analysis, however, demonstrated changes in neuropeptide gene expression and other markers, indicating altered GABAergic neuronal function. Calcium binding protein and GAD65/67 immunohistochemistry showed preserved interneurone populations indicating possible interneurone dysfunction. This was demonstrated by loss of post synaptic GABA receptor markers including gephyrin, GABARAP, and Kif5A, indicating reduced GABAergic synaptic activity. Glutamatergic neuronal signalling was also altered with vesicular glutamate transporter protein and PSD-95 expression being reduced. Changes to the primary visual cortex in DLB indicate that reduced GABAergic transmission may contribute to RCVH in DLB and treatment using targeted GABAergic modulation or similar approaches using glutamatergic modification may be beneficial.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0334-3) contains supplementary material, which is available to authorized users.

Transcriptional network analysis in frontal cortex in Lewy body diseases with focus on dementia with Lewy bodies

“…Other downregulated genes are NETO1, which encodes a protein involved in synaptic N-methyl-D-aspartic acid receptor complexes, and SYP, which encodes SYP, a major synaptic protein. In line with the present findings, loss of post-synaptic GABAreceptor markers has been reported in the occipital cortex in DLB (52). SYP expression was previously reported as decreased in the occipital cortex in DLB as well (67).…”

Classification Accuracy of Transcranial Magnetic Stimulation for the Diagnosis of Neurodegenerative Dementias

“…As SICI and LICI are considered to reflect short‐lasting postsynaptic inhibition mediated through the GABA A and GABA B receptors at the level of local interneurons, and ICF is thought to represent a net facilitation most likely mediated by glutamatergic N‐methyl‐D‐aspartate receptors, the impairment observed in FTD suggests a deficit of GABAergic and glutamatergic interneurons . On the other hand, Aβ peptides have been shown to impair acetylcholine synthesis and release, and to induce cholinergic cell toxicity, which could reflect the impairment of SAI observed in AD .…”

“…As SICI and LICI are considered to reflect short-lasting postsynaptic inhibition mediated through the GABA A and GABA B receptors at the level of local interneurons, 36,37 and ICF is thought to represent a net facilitation most likely mediated by glutamatergic N-methyl-D-aspartate receptors, 11,37 the impairment observed in FTD suggests a deficit of GABAergic and glutamatergic interneurons. [49][50][51] On the other hand, Aβ peptides have been shown to impair acetylcholine synthesis and release, and to induce cholinergic cell toxicity, 52 which could reflect the impairment of SAI observed in AD. [12][13][14][15][16][17][18][19][20][21] In the same view, the well-recognized cholinergic deficit and the documented impairment of GABAergic and glutamatergic neurotransmission in DLB might explain the impairment of both SAI and SICI-ICF in these patients.…”

Review: Clinical, neuropathological and genetic features of Lewy body dementias

“…Neither alpha‐synuclein nor NFT pathology was found in the primary visual cortex of DLB cases and neuronal densities were unchanged. Nevertheless, microarray analysis showed altered GABAergic transmission which may contribute to VH in DLB .…”