Enhanced Dopamine in Prodromal Schizophrenia (EDiPS): a new animal model of relevance to schizophrenia

Abstract

One of the most robust neurochemical abnormalities reported in patients living with schizophrenia is an increase in dopamine (DA) synthesis and release in the dorsal striatum (DS). Importantly, it appears that this increase progresses as a patient transitions from a prodromal stage to the clinical diagnosis of schizophrenia. Here we have recreated this pathophysiology in an animal model by increasing the capacity for DA synthesis preferentially within the DS. To achieve this we administer a genetic construct containing the rate-limiting enzymes in DA synthesis—tyrosine hydroxylase (TH), and GTP cyclohydrolase 1 (GCH1) (packaged within an adeno-associated virus)—into the substantia nigra pars compacta (SNpc) of adolescent animals. We refer to this model as “Enhanced Dopamine in Prodromal Schizophrenia” (EDiPS). We first confirmed that the TH enzyme is preferentially increased in the DS. As adults, EDiPS animals release significantly more DA in the DS following a low dose of amphetamine (AMPH), have increased AMPH-induced hyperlocomotion and show deficits in pre-pulse inhibition (PPI). The glutamatergic response to AMPH is also altered, again in the DS. EDiPS represents an ideal experimental platform to (a) understand how a preferential increase in DA synthesis capacity in the DS relates to “positive” symptoms in schizophrenia; (b) understand how manipulation of DS DA may influence other neurotransmitter systems shown to be altered in patients with schizophrenia; (c) allow researchers to follow an “at risk”-like disease course from adolescence to adulthood; and (d) ultimately allow trials of putative prophylactic agents to prevent disease onset in vulnerable populations.

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

“…Detailed methods regarding the generation of EDiPS animals have been published previously 16 . The EDiPS construct is an AAV2/1-packaged construct containing the human tyrosine hydroxylase (huTH) and human GTP cyclohydrolase 1 (huGCH1) genes, each driven by a human synapsin-1 promoter 16 . This construct is untagged.…”

“…AMPH-induced locomotion was assessed using matt black 60 × 60 × 60 cm chambers, as described previously 16 . Baseline locomotion was recorded for 30 min, then animals were removed and injected with 0.6 mg/kg dexamphetamine (AMPH) intraperitoneally.…”

“…This is especially the case in ARMS cohorts, where trialling novel interventions may be unnecessarily risky for the 80% of patients who would not have transitioned to schizophrenia. Enhanced Dopamine in Prodromal Schizophrenia (EDiPS) is an animal model designed specifically to understand the neurobiology of increased DA synthesis capacity in the prodrome 16 . In this model, an adeno-associated virus (AAV)-packaged genetic construct is delivered at post-natal day 35 (P35).…”

“…The construct is delivered into the substantia nigra pars compacta (SNpc), a dopaminergic region in the midbrain which projects preferentially to the DS 19 . Adult EDiPS animals show an enhanced release of DA preferentially in the DS in response to 0.6 mg/kg amphetamine (AMPH) 16 . This mimics the increased DA synthesis capacity seen so robustly in patients 10 .…”

“…EDiPS is a useful model to investigate the effects of increased DA synthesis and release within the DS on brain connectivity and function, however this model was also designed to study the prodromal phase of schizophrenia. Adult EDiPS animals display increased AMPH-induced hyperlocomotion and deficits in pre-pulse inhibition (PPI) 16 . Therefore, a primary objective of this study was to establish whether these behaviours gradually emerge across adolescence, thus recapitulating the time-course over which the symptoms of schizophrenia emerge in patients.…”