Increased activity of D2 receptors (D2Rs) in the striatum has been linked to the pathophysiology of schizophrenia. To determine directly the behavioral and physiological consequences of increased D2R function in the striatum, we generated mice with reversibly increased levels of D2Rs restricted to the striatum. D2 transgenic mice exhibit selective cognitive impairments in working memory tasks and behavioral flexibility without more general cognitive deficits. The deficit in the working memory task persists even after the transgene has been switched off, indicating that it results not from continued overexpression of D2Rs but from excess expression during development. To determine the effects that may mediate the observed cognitive deficits, we analyzed the prefrontal cortex, the brain structure mainly associated with working memory. We found that D2R overexpression in the striatum impacts dopamine levels, rates of dopamine turnover, and activation of D1 receptors in the prefrontal cortex, measures that are critical for working memory.

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.

The striatum receives prominent dopaminergic innervation that is integral to appetitive learning, performance, and motivation. Signaling through the dopamine D 2 receptor is critical for all of these processes. For instance, drugs with high affinity for the D 2 receptor potently alter timing of operant responses and modulate motivation. Recently, in an attempt to model a genetic abnormality encountered in schizophrenia, mice were generated that reversibly overexpress D 2 receptors specifically in the striatum (Kellendonk et al., 2006). These mice have impairments in working memory and behavioral flexibility, components of the cognitive symptoms of schizophrenia, that are not rescued when D 2 overexpression is reversed in the adult. Here we report that overexpression of striatal D 2 receptors also profoundly affects operant performance, a potential index of negative symptoms. Mice overexpressing D 2 exhibited impairments in the ability to time food rewards in an operant interval timing task and reduced motivation to lever press for food reward in both the operant timing task and a progressive ratio schedule of reinforcement. The motivational deficit, but not the timing deficit, was rescued in adult mice by reversing D 2 overexpression with doxycycline. These results suggest that early D 2 overexpression alters the organization of interval timing circuits and confirms that striatal D 2 signaling in the adult regulates motivational process. Moreover, overexpression of D 2 under pathological conditions such as schizophrenia and Parkinson's disease could give rise to motivational and timing deficits.

To address the role of D1 receptors in the medial prefrontal cortex, we combined pharmacological and genetic manipulations to examine long-term synaptic potentiation (LTP)͞long-term synaptic depression (LTD) in brain slices of rats and mice. We found that the D1 antagonist SCH23390 selectively blocked the maintenance but not the induction of LTP in the prefrontal cortex. Conversely, activation of D1 receptors facilitated the maintenance of LTP, and this effect is impaired in heterozygous D1 receptor knockout mice. Low-frequency stimulation induced a transient depression in the medial prefrontal cortex. This depression could be transformed into LTD by coapplication of dopamine. Coapplication of dopamine, however, shows no facilitating effect on LTD in heterozygous D1 receptor knockout mice. These results provide pharmacological and genetic evidence for a role of D1 receptors in the bidirectional modulation of synaptic plasticity in the medial prefrontal cortex. The absence of this modulation in heterozygous knockout mice shows that a dysregulation of dopamine receptor expression levels can have dramatic effects on synaptic plasticity in the prefrontal cortex.T he prefrontal cortex is thought to be the highest association area in the mammalian cortex and is required for proper executive control. In primates the dorsolateral prefrontal cortex, alone, has been implicated in several different, partly overlapping, cognitive processes, including inhibitory control, working memory, selective attention, attentional-set shifting, rule learning, and strategy switching. In rodents, where the architecture of the cortex is simpler than that of primates, the medial prefrontal cortex (mPFC), the cortex that encompasses the infralimbic and prelimbic areas, is considered to be homologous to the primate dorsolateral prefrontal cortex (1, 2).Consistent with this homology, a variety of studies have shown that dopamine modulates neuronal activity in the prefrontal cortex and affects working memory, attentional performance, attentional-set shifting, and strategy switching (3-9). Some functions of mPFC, such as strategy shifting or rule learning, may be affected by dopaminergic modulation of long-term synaptic plasticity. Dopamine indeed affects long-term plasticity in the prefrontal cortex. It facilitates long-term synaptic depression (LTD) via D1 and D2 receptors (10, 11), and D1 activation has been shown to be required for N-methyl-D-aspartate (NMDA) receptor-dependent long-term synaptic potentiation (LTP) at hippocampal-prefrontal cortex synapses (12).To further our understanding of how dopamine modulates long-term synaptic plasticity in opposite directions, and to develop a model for exploring the underlying molecular signaling pathways, we examined LTP and LTD in slices of the mPFC from rats, wild-type mice, and heterozygous dopamine D1 receptor knockout mice. Heterozygous D1 receptor knockout mice show a 50% reduction in receptor number. They allow us to address specifically the function of the D1 receptor as opposed to both D1 ...