Selective deletion of Caspase-3 gene in the dopaminergic system exhibits autistic-like behaviour

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 104; p. 110030
• Main Authors: García-Domínguez, Irene, Suárez-Pereira, Irene, Santiago, Marti, Pérez-Villegas, Eva M., Bravo, Lidia, López-Martín, Carolina, Roca-Ceballos, María Angustias, García-Revilla, Juan, Espinosa-Oliva, Ana M., Rodríguez-Gómez, José A., Joseph, Bertrand, Berrocoso, Esther, Armengol, José Ángel, Venero, José L., Ruiz, Rocío, de Pablos, Rocío M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 10.01.2021
• Subjects: Autisms; Caspase; Catecholaminergic neurons; Dopaminergic system; Medicin och hälsovetenskap; Tyrosine hydroxylase; Autisms; Caspase; Tyrosine hydroxylase; Catecholaminergic neurons; Dopaminergic system
• ISSN: 0278-5846; 1878-4216; 1878-4216
• DOI: 10.1016/j.pnpbp.2020.110030

Apoptotic caspases are thought to play critical roles in elimination of excessive and non-functional synapses and removal of extra cells during early developmental stages. Hence, an impairment of this process may thus constitute a basis for numerous neurological and psychiatric diseases. This view is especially relevant for dopamine due to its pleiotropic roles in motor control, motivation and reward processing. Here, we have analysed the effect of caspase-3 depletion on the development of catecholaminergic neurons and performed a wide array of neurochemical, ultrastructural and behavioural assays. To achieve this, we performed selective deletion of the Casp3 gene in tyrosine hydroxylase (TH)-expressing cells using Cre-loxP-mediated recombination. Histological evaluation of most relevant catecholaminergic nuclei revealed the ventral mesencephalon as the most affected region. Stereological analysis demonstrated an increase in the number of TH-positive neurons in both the substantia nigra and ventral tegmental area along with enlarged volume of the ventral midbrain. Analysis of main innervating tissues revealed a rather contrasting profile. In striatum, basal extracellular levels and potassium-evoked DA release were significantly reduced in mice lacking Casp3, a clear indication of dopaminergic hypofunction in dopaminergic innervating tissues. This view was sustained by analysis of TH-labelled dopaminergic terminals by confocal and electron microscopy. Remarkably, at a behavioural level, Casp3-deficient mice exhibited impaired social interaction, restrictive interests and repetitive stereotypies, which are considered the core symptoms of autism spectrum disorder (ASD). Our study revitalizes the potential involvement of dopaminergic transmission in ASD and provides an excellent model to get further insights in ASD pathogenesis. •Casp3 gene deletion within TH+ neurons impairs midbrain development.•CASP3 has a key role in shaping the synaptic midbrain connections.•TH-CASP3KO mice display core symptoms of ASD.•TH-CASP3KO mice exhibit dopaminergic hypofunction.•Our study sustains the importance of DA-associated pathways in the aetiology of ASD.