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

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.
This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (SAF2015-64171-R and RTI2018-098645-B-I00). J.A.A. and E.P.V. was supported by a MINECO (BFU2015-64536) grant. I.S.P., E.B. and L.B. were co-financed by the “Fondo Europeo de Desarrollo Regional” (FEDER)-UE “A way to build Europe” from the “Ministerio de Ciencia, Innovación y Universidades” (RTI2018-099778-B-I00) and the Ministerio de Salud-Instituto de Salud Carlos III (PI18/01691), as well as funding from the “Consejería de Salud de la Junta de Andalucía” (PI-0134-2018); the “Programa Operativo de Andalucía FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejería Salud, Junta de Andalucía” (PI-0080-2017); the “Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía” (CTS-510); and the “Centro de Investigación Biomédica en Red de Salud Mental- CIBERSAM” (CB/07/09/0033).