A Possible Role for the Striatum in the Pathogenesis of the Cognitive Symptoms of Schizophrenia

Abstract

The cognitive symptoms of schizophrenia are largely resistant to current treatment and are thus a life-long burden of the illness. Studies of cognitive symptoms have commonly focused on prefrontal cortex because of its demonstrated importance for executive function and working memory—key components of the deficit. The role of striatal-cortical circuitry and therefore the striatum itself has received much less attention. Here we review longstanding evidence that the striatum and its cortical connections are critical for complex cognition and discuss emerging evidence of the striatum’s potential involvement in cognitive symptoms. Finally, we suggest how mouse models might test ideas about the contribution of early striatal dysfunction to the cognitive symptoms of schizophrenia.

Reduced striatal ecto-nucleotidase activity in schizophrenia patients supports the “adenosine hypothesis”

“…We analyzed this cerebral region as some evidence points to the existence of striatal hyperdopaminergic activity secondary to hypofunction of the prefrontal dopamine system [32,33], whereas D 2 R and A 2A R are expressed mainly in medium-sized GABAergic spiny neurons [6]. Interestingly, a recent study showed that, in rodent, ecto-5′-nucleotidase is specifically expressed in this neuronal population, being responsible for most of the extracellular adenosine produced in the striatum [34].…”

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

“…Schizophrenia is typically characterized by three symptom clusters: positive (eg, hallucinations, delusions, disordered thoughts), negative (eg, flattened affects, social withdrawal), and cognitive (eg, attention and working memory deficits) (Simpson et al, 2010). This disease has traditionally been associated with a deregulated dopaminergic system, mainly because of the fact that for many years typical antipsychotics (ie, strong dopamine (DA)-D 2 receptor antagonists such as haloperidol) have served as the mainstream pharmacotherapy for psychotic patients (Keshavan et al, 2008).…”

“…Following the demonstration that loss of function of the 5-HT 2B receptor in Htr 2B − / − mice confers a wide spectrum of schizophrenic-like behavioral phenotypes, we show that selected phenotypes are induced by acute pharmacological blockade of 5-HT 2B receptors with RS127445 (selective 5-HT 2B receptor antagonist) and rescued by chronic antipsychotic treatment with the typical antipsychotic drug haloperidol. The dorsal striatum (dSTR) and its connections with the prefrontal cortex (PFC) have been implicated in the pathogenesis of both the positive and the cognitive symptoms of schizophrenia (Howes et al, 2009;Simpson et al, 2010). Indeed, neurochemical alterations in the dopaminergic and glutamatergic corticostriatal circuits underlie a substantial portion of the dysfunction seen in schizophrenic patients (Gordon, 2010;Howes et al, 2009;Keshavan et al, 2008;Simpson et al, 2010).…”

Copy number deletion burden is associated with cognitive, structural, and resting-state network differences in patients with schizophrenia

“…There was a negative correlation between connectivity between the mPFC M a n u s c r i p t 18 and the left iPFC and performance IQ. Prefrontal striatal connectivity has been linked with cognitive functioning in schizophrenia [71,72] as well as in other populations [73][74][75]. The striatum and cortex are anatomically and functionally linked through several cortico-striatal-thalamic-cortical circuits [76] and pathologies of the striatum affect cognition in a similar manner to pathologies of the prefrontal cortex [77].…”