Positive symptom phenotypes appear progressively in “EDiPS”, a new animal model of the schizophrenia prodrome

Abstract

An increase in dopamine (DA) synthesis capacity in the dorsal striatum (DS) during the prodromal stage of schizophrenia becomes more pronounced as patients progress to the full disorder. Understanding this progression is critical to intervening in disease course. We developed an animal model—Enhanced Dopamine in Prodromal Schizophrenia (EDiPS)—which uses a genetic construct to increase DA synthesis capacity in the DS of male rats. We assessed pre-pulse inhibition (PPI) and amphetamine (AMPH)-induced locomotion (0.6 mg/kg) in EDiPS animals longitudinally after post-natal day 35 (when the EDiPS construct is administered). We also assessed their response to repeated acute restraint stress. In adult EDiPS animals, we measured baseline and evoked extracellular DA levels, and their stereotyped responses to 5 mg/kg AMPH. AMPH-induced hyperlocomotion was apparent in EDiPS animals 6-weeks after construct administration. There was an overall PPI deficit in EDiPS animals across all timepoints, however the stress response of EDiPS animals was unaltered. Adult EDiPS animals show normal baseline and potassium-evoked DA release in the DS. These findings suggest that key behavioural phenotypes in EDiPS animals show a progressive onset, similar to that demonstrated by patients as they transition to schizophrenia. The EDiPS model could therefore be used to investigate the molecular mechanisms underlying the prodrome of schizophrenia.

Animal Models of Relevance to the Schizophrenia Prodrome

“…Adult EDiPS animals also display increased amphetamine-induced hyperlocomotion and prepulse inhibition (PPI) deficits ( 46 ). When assessed longitudinally from juvenile to adult ages, these behaviors show a progressive onset, similar to the progression of symptoms seen in prodromal patients ( 47 ). This model can now be used to clarify the downstream effects of increased dopamine synthesis and release during adolescence.…”

Activity in the Dorsomedial Striatum Underlies Serial Reversal Learning Performance Under Probabilistic Uncertainty

“…Psychomimetic drugs such as amphetamine are often used to model the increased dopaminergic function associated with psychosis ( 15 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ). However, increasing brain dopaminergic function did not alter the number of reversals per 100 trials ( Figure 3A ), the response latency ( Figure 3B ), or the win-stay probability ( Figure 3C ) during reversal learning.…”

Increasing dopamine synthesis in nigrostriatal circuits increases phasic dopamine release and alters dorsal striatal connectivity: implications for schizophrenia

“…Moreover, its behavioural phenotypes of relevance to the positive symptoms of schizophrenia emerge progressively from adolescence to early adulthood, mimicking the temporal onset of symptoms in patients 35 . Together, these outcomes make this model ideal to study the prodromal onset of this disorder 21 , 22 . Now we extend the applicability of this model to understand how increasing DA synthesis selectively within the DS affects tonic/phasic DA release.…”

“…This model is referred to as EDiPs (Enhanced Dopamine in Prodromal schizophrenia). By delivering the two rate-limiting enzymes in DA synthesis (GTP cyclohydrolase 1 and tyrosine hydroxylase) to the pars compact of the substantia nigra, we have produced a model producing a selective increase in DA release in the DS in response to low dose amphetamine, and impaired pre-pulse inhibition as observed in patients 21 , 22 . This model also reproduces an increase in Glx in the DS 21 .…”