A schizophrenia risk factor induces marked anatomical deficits at GABAergic-dopaminergic synapses in the rat ventral tegmental area: Essential evidence for new targeted therapies.

Autor: Seo S; Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.; Brain Health Research Centre, University of Otago, Dunedin, New Zealand., Sizemore RJ; Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.; Brain Health Research Centre, University of Otago, Dunedin, New Zealand., Reader KL; Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.; Brain Health Research Centre, University of Otago, Dunedin, New Zealand., Smither RA; Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.; Brain Research, New Zealand., Wicky HE; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.; Brain Research, New Zealand.; Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand., Hughes SM; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.; Brain Research, New Zealand.; Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand., Bilkey DK; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.; Department of Psychology, University of Otago, Dunedin, New Zealand., Parr-Brownlie LC; Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.; Brain Research, New Zealand., Oorschot DE; Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
Jazyk: angličtina
Zdroj: The Journal of comparative neurology [J Comp Neurol] 2021 Dec; Vol. 529 (18), pp. 3946-3973. Date of Electronic Publication: 2021 Sep 01.
DOI: 10.1002/cne.25225
Abstrakt: To develop new therapies for schizophrenia, evidence accumulated over decades highlights the essential need to investigate the GABAergic synapses that presynaptically influence midbrain dopaminergic neurons. Since current technology restricts these studies to animals, and evidence accumulated in recent decades indicates a developmental origin of schizophrenia, we investigated synaptic changes in male rat offspring exposed to maternal immune activation (MIA), a schizophrenia risk factor. Using a novel combination of lentiviruses, peroxidase-immunogold double labeling, three-dimensional serial section transmission electron microscopy and stereology, we observed clear anatomical alterations in synaptic inputs on dopaminergic neurons in the midbrain posterior ventral tegmental area (pVTA). These changes relate directly to a characteristic feature of schizophrenia: increased dopamine release. In 3-month-old and 14-month-old MIA rats, we found a marked decrease in the volume of presynaptic GABAergic terminals from the rostromedial tegmental nucleus (RMTg) and in the length of the synapses they made, when innervating pVTA dopaminergic neurons. In MIA rats in the long-term, we also discovered a decrease in the volume of the postsynaptic density (PSD) and in the maximum thickness of the PSD at the same synapses. These marked deficits were evident in conventional GABA-dopamine synapses and in synaptic triads that we discovered involving asymmetric synapses that innervated RMTg GABAergic presynaptic terminals, which in turn innervated pVTA dopaminergic neurons. In triads, the PSD thickness of asymmetric synapses was significantly decreased in MIA rats in the long-term cohort. The extensive anatomical deficits provide a potential basis for new therapies targeted at synaptic inputs on midbrain pVTA dopaminergic neurons, in contrast to current striatum-targeted antipsychotic drugs.
(© 2021 Wiley Periodicals LLC.)
Databáze: MEDLINE
Externí odkaz: