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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    187—Decision Making: Prefrontal Cortex

    Sunday, November 10, 2013, 8:00 am - 12:00 noon

    187.24: Prefrontal GABA receptor modulation of performance of a massed-trials version of the radial arm maze

    Location: Halls B-H

    Dept Psychology, Univ. of British Columbia, Vancouver, BC, Canada

    Abstract Body: Prefrontal cortical GABA transmission is thought to play a key role in regulation of cognitive functions governed by the frontal lobes. Notably, alterations in markers of prefrontal GABA function are one of the most reliable pathologies observed in schizophrenia. Although it has been proposed that such alterations may underlie impairments associated with the disorder, there has been relatively little research on how diminished prefrontal GABA signaling alters cognition. Recent work from our group revealed that blockade of GABAA receptors in the medial prefrontal cortex (mPFC) recapitulates many aspects of schizophrenia in the rat. Interestingly, working memory assessed with a delayed-response version of the radial arm maze task was not impaired by these manipulations. However, tasks used to examine working memory in schizophrenics find deficits when multiple trials are presented in quick succession, and resistance to proactive interference is required. Thus, the goal of the present study was to address whether this aspect of cognition is impaired by prefrontal GABAA antagonism. Rats were trained in a massed trials-version of the working/reference memory version of the task. Schizophrenic subjects display performance deficits when tested on a virtual version of this radial-maze task. Here, rats were required to retrieve a food from the same four arms of an eight arm maze and then were subjected 5 repeated trials per day (1-2 min ITI). This procedure increases proactive interference, as subjects must discard information from previous trials. After extended training, rats received intra-mPFC infusions of bicuculline (12.5 or 50 ng) or saline on separate test days. PFC GABAA receptor blockade caused a profound increase in both working and reference memory errors on both the first and subsequent trials, and also increased response latencies. In a second study, we addressed whether PFC inactivation impaired performance in the massed trials-version of the task. In stark contrast to the above-mentioned findings, infusions of the GABA agonists baclofen and muscimol (100 ng each) did not impair performance on the first trial, and caused only a modest increase in reference memory errors on subsequent trials. Taken together, these results demonstrate that hypofunction of prefrontal GABA leads to a severe impairment in radial arm maze performance that is 1) distinct from the effect of PFC inactivation and 2) mirrors deficits described in schizophrenic patients.

    Lay Language Summary: Our results demonstrate that diminished inhibitory GABA signaling in the prefrontal cortex can markedly impair certain forms of cognition that are known to be affected in schizophrenia. As such, these data important preclinical evidence to suggest that cognitive dysfunction in schizophrenia is due in part to disruptions of inhibitory transmission within the frontal lobes.
    Cognitive deficits are amongst the most debilitating aspects of schizophrenia, and the severity of cognitive symptoms has been shown to predict patient quality of life. Furthermore, while currently available antipsychotic medications show efficacy against the “positive” symptoms of schizophrenia (i.e. hallucinations and delusions), they are not effective in treating cognitive symptoms. Obtaining a better understanding of the origin of cognitive deficits associated with schizophrenia is thus crucial, as it may aid in the discovery of new therapies. Alterations in markers of GABA signaling are one of the most reliable pathologies found in post-mortem studies of schizophrenic brain, and it has been proposed that abnormalities in GABA signaling within the prefrontal cortex may contribute to cognitive impairments in schizophrenia. However, surprisingly little research has been done examining the direct contribution of prefrontal GABA signaling to cognition.
    Here, we took the relatively straightforward approach of reducing GABA transmission in the prefrontal cortex using local administration of a GABA-A receptor antagonist. We examined how this affected performance of a version of a radial arm maze task. Previous studies of schizophrenic patients have shown that these individuals exhibit great difficulty when performing a near-identical “virtual” version of this task. In our study, rats were trained to retrieve a food reward from the same four arms of an eight-arm maze, and then were subjected to training where several trials were presented in close succession. We found that reducing prefrontal GABA transmission profoundly impaired performance both on the first and subsequent trials of the task. Moreover, the nature of this impairment was strikingly similar to that observed in schizophrenic patients performing a virtual version of this task. Reducing inhibitory transmission in the prefrontal cortex increased both short-term (“working) and long-term (“reference”) memory errors and reduced speed of processing (indexed by choice latencies), similar to what has been observed in patients.
    A subsequent experiment addressed important questions regarding the specific involvement of the prefrontal cortex in this task. To this end, we tested the effect of temporary inactivation of the prefrontal cortex, effectively the opposite to the above GABA receptor blockade. In stark contrast to what was observed after prefrontal disinhibition, inactivation of this region did not affect any measure of performance. This result is particularly intriguing, as it suggests that while the prefrontal cortex may not directly be involved in radial arm maze performance, a loss of inhibition, inducing a “noisy” cortex can nevertheless hamper cognitive operations required when using short and long-term spatial memory to guide behavior, perhaps by interfering with the function of other circuits necessary for performance of the task.
    Our results indicate that optimal GABA signaling within the PFC is necessary for the performance of cognitive tasks dependent on working and spatial reference memory. Impaired GABA signaling leads to cognitive deficits that are nearly identical to those observed in schizophrenic patients. Taken together with our previous work, it appears that prefrontal GABA receptor blockade recapitulates several aspects of schizophrenia. These findings provide important confirmation that the deficits observed in the disorder may be driven by a “noisy” frontal lobe that may interfere with a variety of cognitive functions, including those not normally mediated by the prefrontal cortex. Furthermore, these findings indicate that this approach may be a useful model for testing potential pro-cognitive drugs in the future.