Brain and Spine Institute. France: The Biotechnology & Biotherapy team, created by Dr. Jacques Mallet and presently directed
by Dr. Philippe Ravassard, at the Brain and Spine Institute (ICM), in collaboration with the
Pole of Therapeutic Innovation in Neuropsychiatry at the Servier Research Institute, has
shown that the local inactivation of Gpr88, a new receptor expressed exclusively in the
brain, normalizes some behaviors altered in a model of schizophrenia.
This work, conducted
by Manuela Ingallinesi for her Ph.D. thesis under the scientific direction of Dr. Rolando
Meloni, constitutes an important breakthrough in the validation of Gpr88 as a novel
therapeutic target as well as an innovative experimental approach for the treatment of
schizophrenia. This study has been published August 26th 2014 in Molecular Psychiatry one
of the leading journals in psychiatric research.
Schizophrenia, characterized by positive, negative and cognitive symptoms, is a serious and
handicapping mental illness affecting about 1% of the population.
The current therapies are
essentially based on neuroleptics that allow for managing positive symptoms such as
delusions and hallucinations, as well as negative symptoms such as blunted affect and lack of
emotions, but are less effective against cognitive deficits, characterized by disorganized
thinking. Moreover, up to one third of the patients do not respond to these therapies.
Therefore, new therapeutic targets are actively sought for improving the treatment of
schizophrenia symptoms, particularly cognitive deficits.
Gpr88 is a receptor with an unknown role that is expressed almost exclusively in the striatum,
a brain structure deeply implicated in neuropsychiatric diseases. The complete deletion of
Gpr88 in the striatum of genetically modified mice causes behavioral alterations associated to
schizophrenia.
The interest of the Biotechnology and Biotherapy team for Gpr88 stems from
the work of Drs Meloni and Mallet in psychiatric genetic showing that the gene coding for
Gpr88 is associated as a risk factor with schizophrenia.
To address the biological basis of this association, the researchers under the direction of Dr.
Meloni have assessed the role of Gpr88 using an animal model of schizophrenia generated by
treating newborn rats with phencyclidine, a drug of abuse that provokes in the adult animal
behavioral alterations reproducing the symptoms of schizophrenia.
Thereafter, the
researchers have injected by microsurgery a lentiviral vector expressing a microRNA (miR) in
the Nucleus Accumbens of these animals to knock-down Gpr88. The Nucleus Accumbens is a
brain structure, localized in the ventral part of the striatum, whose function is deeply altered
in the course of schizophrenia. The miRs are RNA sequences that, through complementary pairing, trigger the degradation and prevent the translation to a protein of the messenger RNA
expressed by the targeted gene.
Interestingly the localized knock-down of Gpr88 in the Nucleus Accumbens, contrary to the
complete deletion in the entire brain, significantly reduces the behavioral alterations
associated to the schizophrenia model. Notably, a normal behavior in a social cognition test is
reestablished by the inactivation of Gpr88 in the Nucleus Accumbens. Thus, these results show
that Gpr88 is a novel potential target of great interest for the treatment of schizophrenia that
may take care of the cognitive deficits refractory to the currently used drugs. Moreover, the
approach that they have developed underscores the interest of miRs for characterizing targets
with unknown functions.
Finally, this study represents an important breakthrough for the
therapeutic utilization, by intracerebral transfer, of lentiviral vectors in mental diseases.