| Abstract: | There is strong evidence that the core deficits of schizophrenia result from dysfunction of the dopamine (DA) system, but details of this dysfunction remain unclear. We previously reported a model of transgenic mice that selectively and reversibly overexpress DA D2 receptors (D2Rs) in the striatum (D2R-OE mice). D2R-OE mice display deficits in cognition and motivation that are strikingly similar to the deficits in cognition and motivation observed in patients with schizophrenia. Here, we show that in vivo, both the firing rate (tonic activity) and burst firing (phasic activity) of identified midbrain DA neurons are impaired in the ventral tegmental area (VTA), but not in the substantia nigra (SN), of D2R-OE mice. Normalizing striatal D2R activity by switching off the transgene in adulthood recovered the reduction in tonic activity of VTA DA neurons, which is concordant with the rescue in motivation that we previously reported in our model. On the other hand, the reduction in burst activity was not rescued, which may be reflected in the observed persistence of cognitive deficits in D2R-OE mice. We have identified a potential molecular mechanism for the altered activity of DA VTA neurons in D2R-OE mice: a reduction in the expression of distinct NMDA receptor subunits selectively in identified mesolimbic DA VTA, but not nigrostriatal DA SN, neurons. These results suggest that functional deficits relevant for schizophrenia symptoms may involve differential regulation of selective DA pathways.Deficits in cognition and motivation are core features of schizophrenia (1, 2). These symptoms are listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition as a diagnostic criterion for schizophrenia spectrum disorder (3) and have a significant impact on patients’ overall functioning and quality of life (4, 5). Currently, there are no effective treatments for these disabling aspects of the disease. Therefore, a high priority in the study of schizophrenia is to increase our understanding of the neurobiology of cognitive and motivational deficits. The midbrain dopamine (DA) system affects cognition and motivation in healthy subjects. It includes DA neurons of the ventral tegmental area (VTA), projecting to prefrontal cortex (PFC) and limbic areas (e.g., ventral striatum), and DA neurons of the substantia nigra (SN), projecting to the dorsal striatum (6). Involvement of the midbrain DA system is strongly implicated in both the cognitive and motivational deficits observed in schizophrenia (7, 8). Moreover, it is well documented that the DA system is altered in patients with schizophrenia (reviewed in refs. 9, 10).To model the increase in striatal DA D2 receptor (D2R) activity observed in patients with schizophrenia, we previously generated transgenic mice that selectively and reversibly overexpress D2Rs in the striatum (D2R-OE mice) (11). In this model, expression of the transgenic D2Rs is restricted to the postsynaptic medium spiny neurons in the striatum and can be temporally regulated. D2R-OE mice display phenotypes strikingly similar to the cognitive and negative symptoms of schizophrenia. Cognitive phenotypes of D2R-OE mice include deficits in working memory tasks, behavioral flexibility, conditional associative learning, and timing (11–14). D2R-OE mice also exhibit phenotypes similar to the negative symptoms of schizophrenia: a deficit in incentive motivation, without disruption of hedonic processes (13, 15–17). We previously reported that these behavioral deficits in striatal D2R-OE mice are accompanied by changes in cortical DA function (11, 18). D2R overexpression restricted to the striatum led to alterations in DA function in the PFC. These alterations include changes in both the amount and rate of turnover of DA in PFC tissue, as well as changes in the activation of D1 receptors in the PFC in vivo. We also identified changes in inhibitory transmission and DA sensitivity in the PFC of D2R-OE mice (18).The finding that increased D2R expression restricted to the striatum leads to changes in DA function in the cortex suggests that a central component of the DA midbrain system is perturbed in the D2R-OE mice. We therefore set out to determine whether these changes might be occurring at the level of presynaptic DA neuron activity. To determine if increased postsynaptic D2R activity in the striatum has an impact on the electrophysiological activity of DA midbrain neurons, we performed single-unit extracellular recordings and juxtacellular labeling of individual DA midbrain neurons in vivo from D2R-OE mice and their control littermates. We found that increased D2R activity in the striatum changed the electrophysiological properties of DA neurons in the VTA, whereas DA neurons in the SN remained unaffected. Specifically, we found that in the DA VTA neurons, both the firing frequency and burst activity were reduced in D2R-OE mice compared with controls. When we switched off the transgene in adulthood, the firing frequency was rescued but the decrease in burst activity was not. This dissociation of the two phenotypes may reflect potentially reversible and irreversible components of DA pathophysiology. In vivo burst activity of DA neurons is under powerful control of NMDA receptor currents (19, 20). To investigate a potential molecular mechanism for the observed alterations in the activity of DA neurons, we quantified NMDA receptor subunit mRNA levels in DA neurons of both the mesolimbic and nigrostriatal pathways. Consistent with the electrophysiological deficits, we found a specific reduction of NMDA receptor subunit 1 (NR1) and NR2B expression selectively in mesolimbic DA neurons of the VTA in D2R-OE mice. |
