Modelling prefrontal cortex deficits in schizophrenia: implications for treatment

Abstract

Current treatments of schizophrenia are compromised by their inability to treat all symptoms of the disease and their sideeffects. Whilst existing antipsychotic drugs are effective against positive symptoms, they have negligible efficacy against the prefrontal cortex (PFC)-associated cognitive deficits and negative symptoms. New models that reproduce core pathophysiological features of schizophrenia are more likely to have improved predictive validity in identifying new treatments. We have developed a NMDA receptor antagonist model that reproduces core PFC deficits of schizophrenia and discuss this in relation to pathophysiology and treatments. Subchronic and chronic intermittent PCP (2.6 mg/kg i.p.) was administered to rats. PFC activity was assessed by 2-deoxyglucose imaging, parvalbumin and Kv3.1 mRNA expression, and the attentional set-shifting test (ASST) of executive function. Affymetrix gene array technology was employed to examine gene expression profile patterns. PCP treatment reduced glucose utilization in the PFC (hypofrontality). This was accompanied by a reduction in markers of GABAergic interneurones (parvalbumin and Kv3.1 mRNA expression) and deficits in the extradimensional shift dimension of the ASST. Consistent with their clinical profile, the hypofrontality was not reversed by clozapine or haloperidol. Transcriptional analysis revealed patterns of change consistent with current neurobiological theories of schizophrenia. This model mirrors core neurobiological deficits of schizophrenia; hypofrontality, altered markers of GABAergic interneurone activity and deficits in executive function. As such it is likely to be a valuable translational model for understanding the neurobiological mechanisms underlying hypofrontality and for identifying and validating novel drug targets that may restore PFC deficits in schizophrenia.

Severe Cross-Modal Object Recognition Deficits in Rats Treated Sub-Chronically with NMDA Receptor Antagonists are Reversed by Systemic Nicotine: Implications for Abnormal Multisensory Integration in Schizophrenia

“…Indeed, sub-chronic treatment with PCP or ketamine has been reported to decrease GABAergic markers and glucose utilization in the rat prefrontal cortex (Cochran et al, 2003;Pratt et al, 2008), consistent with observed prefrontal dysfunction in patients with schizophrenia (Lewis and Gonzalez-Burgos, 2008).…”

“…There is ample evidence that sub-chronic NMDAR antagonist treatment affects parvalbumin-containing GABAergic inhibitory interneurons in the cortex, and these interneurons may be critical to oscillatory activity central to cognitive functions (Cochran et al, 2003;Nakazawa et al, 2012;Pratt et al, 2008); similar deficiencies are observed in the brains of patients with schizophrenia (Lewis et al, 2012). In the absence of this oscillatory control, synchronous information processing in the cortex may be disrupted.…”

Identification of Targeted Analyte Clusters for Studies of Schizophrenia

“…We then generated Gaussian kernel projections for the data using the same settings as for the human studies. This showed that the acute and chronic PCP rat models, which are used routinely in studies of schizophrenia (26), gave high predictive results with precisions of greater than 80% (Fig. 5).…”

Neurocognitive Expression of Hypofrontality in Long Term Schizophrenia

“…There are two pharmacological models of the NMDA-R (receptor) hypofunction -acute and chronic (Pratt et al, 2008). Acute receptor antagonist model relates to a short-term administration of the NMDA-R antagonist.…”

“…Also, a significant increase of the glutaminic acid concentration in the cingular area has been noted both in patients with an early psychosis (Théberge et al, 2002), and with prodromal schizophrenia symptoms (Stone et al, 2009). Pratt et al (2008) proposed a chronic psylocybine (PCP) model, which explains a relation between the NMDA receptors hypofunction and hypofrontality. Chronic administration of the PCP to rats caused a reduction of glucose metabolism in their prefrontal cortex, and a decrease in the expression of protein marker of gamma aminobutyric acid (GABA) interneuron's' activity.…”