Spliceozymes: Ribozymes that Remove Introns from Pre-mRNAs in Trans

Group I introns are pre-mRNA introns that do not require the spliceosome for their removal. Instead, they fold into complex three-dimensional structures and catalyze two transesterification reactions, thereby excising themselves and joining the flanking exons. These catalytic RNAs (ribozymes) have been modified previously to work in trans, whereby the ribozymes can recognize a splice site on a substrate RNA and replace the 5'- or 3'-portion of the substrate. Here we describe a new variant of the group I intron ribozyme from Tetrahymena that recognizes two splice sites on a substrate RNA, removes the intron sequences between the splice sites, and joins the flanking exons, analogous to the action of the spliceosome. This 'group I spliceozyme' functions in vitro and in vivo, and it is able to mediate a growth phenotype in E. coli cells. The intron sequences of the target pre-mRNAs are constrained near the splice sites but can carry a wide range of sequences in their interior. Because the splice site recognition sequences can be adjusted to different splice sites, the spliceozyme may have the potential for wide applications as tool in research and therapy

Latent Inhibition-Related Dopaminergic Responses in the Nucleus Accumbens are Disrupted Following Neonatal Transient Inactivation of the Ventral Subiculum

Schizophrenia would result from a defective connectivity between several integrative regions as a consequence of neurodevelopmental failure. Various anomalies reminiscent of early brain development disturbances have been observed in patients' left ventral subiculum of the hippocampus (SUB). Numerous data support the hypothesis of a functional dopaminergic dysregulation in schizophrenia. The common target structure for the action of antipsychotics appears to be a subregion of the ventral striatum, the dorsomedial shell part of the nucleus accumbens. Latent inhibition, a cognitive marker of interest for schizophrenia, has been found to be disrupted in acute patients. The present study set out to investigate the consequences of a neonatal functional inactivation of the left SUB by tetrodotoxin (TTX) in 8-day-old rats for the latent inhibition-related dopaminergic responses, as monitored by in vivo voltammetry in freely moving adult animals (11 weeks) in the left core and dorsomedial shell parts of the nucleus accumbens in an olfactory aversion procedure. Results obtained during the retention session of a three-stage latent inhibition protocol showed that the postnatal unilateral functional blockade of the SUB was followed in pre-exposed TTX-conditioned adult rats by a disruption of the behavioral expression of latent inhibition and induced a total and a partial reversal of the latent inhibition-related dopaminergic responses in the dorsomedial shell and core parts of the nucleus accumbens, respectively. The present data suggest that neonatal inactivation of the SUB has more marked consequences for the dopaminergic responses recorded in the dorsomedial shell part, than in the core part of the nucleus accumbens. These findings may provide new insight into the pathophysiology of schizophrenia