Evidence supports a dysregulation of subcortical dopamine (DA) system function as a common etiology of psychosis; however, the factors responsible for this aberrant DA system responsivity have not been delineated. Here, we demonstrate in an animal model of schizophrenia that a pathologically enhanced drive from the ventral hippocampus (vHipp) can result in aberrant dopamine neuron signaling. Adult rats in which development was disrupted by prenatal methylazoxymethanol acetate (MAM) administration display a significantly greater number of spontaneously firing ventral tegmental DA neurons. This appears to be a consequence of excessive hippocampal activity because, in MAM-treated rats, vHipp inactivation completely reversed the elevated DA neuron population activity and also normalized the augmented amphetamine-induced locomotor behavior. These data provide a direct link between hippocampal dysfunction and the hyper-responsivity of the DA system that is believed to underlie the augmented response to amphetamine in animal models and psychosis in schizophrenia patients.
Decreased GABAergic signaling is among the more robust pathologies observed postmortem in schizophrenia; however, the functional consequences of this deficit are still largely unknown. Here, we demonstrate, in a verified animal model of schizophrenia, that a reduced expression of parvalbumin (PV)-containing interneurons is correlated with a reduction in coordinated neuronal activity during task performance in freely moving rats. More specifically, methylazoxymethanol acetate (MAM)-treated rats display a decreased density of parvalbumin-positive interneurons throughout the medial prefrontal cortex (mPFC) and ventral (but not dorsal) subiculum of the hippocampus. Furthermore, the reduction in interneuron functionality is correlated with a significantly reduced gamma-band response to a conditioned tone during a latent inhibition paradigm. Finally, deficits in mPFC and ventral hippocampal oscillatory activity are associated with an impaired behavioral expression of latent inhibition in MAM-treated rats. Thus, we propose that a decrease in intrinsic GABAergic signaling may be responsible, at least in part, for the prefrontal and hippocampal hypofunctionality observed during task performance, which is consistently observed in animal models as well as in schizophrenia in humans. In addition, a deficit in intrinsic GABAergic signaling may be the origin of the hippocampal hyperactivity purported to underlie the dopamine dysfunction in psychosis. Such information is central to gaining a better understanding of the disease pathophysiology and alternate pharmacotherapeutic approaches.
Substantial evidence suggests that psychosis in schizophrenia is associated with a dysregulation of subcortical dopamine system function. Here we examine evidence that this dysregulation is secondary to hyperactivity within hippocampal subfields. Enhanced hippocampal activity has been reported in both preclinical models and in schizophrenia patients. Moreover, this hippocampal hyperactivity is correlated with enhanced dopamine neuron activity and positive symptoms, respectively. Thus, restoration of hippocampal function could provide a more effective therapeutic approach than current therapeutics based on dopamine D2 receptor blockade. Indeed, initial studies demonstrate that allosteric modulation of the α5GABAA receptor can decrease aberrant dopamine signaling and associated behaviors in a verified rodent model of psychosis.
In response to behaviorally salient stimuli, dopamine (DA) neurons fire in bursts. Burst firing induces a large transient increase in synaptic DA and is regarded as the functionally relevant mode of transmission that signals reward and modulates goal-directed behavior. DA neuron burst firing is dynamically regulated by afferent inputs, and it is not present in vitro because of severing of afferent processes. However, what afferents are requisite for burst firing in vivo is not known. Here, we show that tonic input from the laterodorsal tegmental nucleus (LDTg) is required for glutamateelicited burst firing in ventral tegmental area DA neurons of anesthetized rats. Also, after LDTg inactivation, DA neurons fire as they do in vitro (i.e., as pacemakers); even direct glutamate application fails to cause them to burst fire under these conditions. These data show that the LDTg is critical to normal DA function, and thus, pathology within this region may lead to aberrant DA signaling.electrophysiology ͉ laterodorsal tegmental nucleus ͉ firing pattern ͉ limbic system
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