Líneas de investigación

• Neurobiological basis of fast-acting antidepressant strategies

  We aim to identify brain circuits involved in fast-acting antidepressant strategies, such as deep brain stimulation or ketamine, which act primarily by modulating excitatory glutamatergic neurotransmission. According to recent results from the group, some of these strategies act by rapidly stimulating serotonergic neurotransmission via activation of glutamate AMPA receptors in ventral prefrontal cortex neurons projecting to midbrain. This appears to be a more efficient way than blocking serotonin reuptake, as produced by classic antidepressant drugs.

• Use of RNA interference (RNAi) as a translational strategy in the study of major depressive disorder

  We are using RNAi strategies in vivo in order to modulate the expression of genes involved in the pathophysiology and treatment of major depressive disorder. We have developed a translational strategy by synthesizing conjugated siRNA (small interfering RNA) or ASO (antisense oligonucleotide) molecules to selectively knockdown genes expressed in serotonergic, noradrenergic and/or dopaminergic neurons after intranasal administration. On the other hand, the siRNA-induced knockdown of the astroglial glutamate transporters GLT-1 and GLAST in ventral areas of the mouse prefrontal cortex evokes a robust depressive phenotype reversed by antidepressant treatments.

• Role of synucleins in the modulation of monoaminergic neurotransmission: involvement in psychiatric and cognitive aspects of Parkinson’s disease

  Using models of AAV vector-induced overexpression or of RNAi-induced knockdown of α- and γ-synucleins, we are studying their physiological role in the control of synaptic function as well as their role in the emergence of pre-motor (cognitive, psychiatric) symptoms of Parkinson’s disease. The results obtained so far indicate that α- and γ-synuclein act as negative regulators of monoamine (serotonin, dopamine) neurotransmission in rodent brain, thus contributing to non-motor symptoms of Parkinson’s disease.

• Mechanism of action of antidepressant and antipsychotic drugs: identification of new therapeutic targets and brain circuits involved

  As a general objective of the group, we aim at identifying the brain circuits involved in the therapeutic action of drugs used to treat major depression and psychosis (schizophrenia).  In recent years we have characterized the action of non-competitive NDMA receptor antagonists, used as pharmacological models of schizophrenia, on thalamo-cortical circuits, and the reversal of these actions by antipsychotic treatments. Likewise, we have recently characterized the involvement of reciprocal networks between ventral areas of the prefrontal cortex (infralimbic cortex) and the serotonergic raphe nuclei in the emergence of depressive-like phenotypes and in antidepressant actions of glutamatergic agents.