Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

Abstract

A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.

Molecular signature of extracellular matrix pathology in schizophrenia

“…For example, expression of ADAMTS2, which was upregulated across all brain regions examined in our study, was increased in peripheral blood samples from subjects with SZ, and decreased following antipsychotic treatment (Ruso‐Julve et al., 2019; Sainz et al., 2019). Furthermore, antipsychotics were shown to inhibit dopamine‐induced expression of ADAMTS2 in neuronal cell culture, suggesting that antipsychotics partially correct for increased ADAMTS2 expression that we observed in subjects with SZ (Ruso‐Julve et al., 2019).…”

“…Antipsychotics, lithium and VPA have all been reported to impact ECM molecules in rodent and human studies. In many cases, the effects of these drugs are opposite to changes observed in subjects with SZ, suggesting that these treatments may achieve therapeutic efficacy in part by correcting for changes in ECM molecules (Ruso‐Julve et al., 2019; Sainz et al., 2019; Yukawa et al., 2018). For example, expression of ADAMTS2, which was upregulated across all brain regions examined in our study, was increased in peripheral blood samples from subjects with SZ, and decreased following antipsychotic treatment (Ruso‐Julve et al., 2019; Sainz et al., 2019).…”

“…In many cases, the effects of these drugs are opposite to changes observed in subjects with SZ, suggesting that these treatments may achieve therapeutic efficacy in part by correcting for changes in ECM molecules (Ruso‐Julve et al., 2019; Sainz et al., 2019; Yukawa et al., 2018). For example, expression of ADAMTS2, which was upregulated across all brain regions examined in our study, was increased in peripheral blood samples from subjects with SZ, and decreased following antipsychotic treatment (Ruso‐Julve et al., 2019; Sainz et al., 2019). Furthermore, antipsychotics were shown to inhibit dopamine‐induced expression of ADAMTS2 in neuronal cell culture, suggesting that antipsychotics partially correct for increased ADAMTS2 expression that we observed in subjects with SZ (Ruso‐Julve et al., 2019).…”

CBD Effects on Motor Profile and Neurobiological Indices Related to Glutamatergic Function Induced by Repeated Ketamine Pre-Administration

“…These few reports supporting that CBD attenuates aberrant status of ERK1/2 phosphorylation which is related to schizophrenia-related symptomatology, converge with studies regarding antipsychotic drugs effect on p-ERK1/2. In particular it is shown that antipsychotics per se induce opposite effects of p-ERK state as compared to p-ERK alterations in psychosis or schizophrenia models ( Ruso-Julve et al, 2019 ). These reports concerning antipsychotic action on p-ERK are in line with present findings concerning CBD effects.…”

Non-Coding RNAs in Psychiatric Disorders and Suicidal Behavior

“…Of them, miR-132 was highly expressed in the forebrain and was regulated by cAMP response element-binding (CREB) and extracellular signal regulated kinase (ERK) signaling. Both CREB and ERK are targets of antipsychotic drugs ( 91 , 116 ). On the contrary, Miller et al.…”