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Prefrontal cortical GABAergic regulation of cognition : implications for schizophrenia & other psychiatric disorders

University of British Columbia

Deficient GABA signalling in the frontal lobes has been posited as a pathophysiological mechanism underlying symptoms and cognitive impairments in schizophrenia and other psychiatric disorders. Yet, there has been a lack of basic research assessing how decreased prefrontal cortex (PFC) GABAergic transmission impacts cognition. The experiments described here were aimed at elucidating how PFC GABA signalling regulates working memory and attention, two core cognitive processes altered in psychiatric conditions. In the first experiment, pharmacological reduction of PFC GABAA receptor transmission led to delay-independent deficits in working memory, suggesting that PFC GABA signalling may be particularly important for working memory encoding, while PFC NMDA glutamatergic transmission appears to be necessary for working memory maintenance. Given that attention strongly influences encoding, the next experiment identified separable attentional processes modulated by PFC GABAergic transmission. In addition to disrupting attention, PFC GABA dysfunction may contribute to working memory deficits by impairing filtering of distracting information. In the third study, PFC GABAergic regulation of resistance to proactive interference from past information was examined in a massed-trials variant of the reference/working radial maze task. While PFC GABAA antagonism did not increase proactive interference effects, strong impairments in working and reference memory were found across the test session. PFC inactivation did not affect performance, indicating that disinhibition of the PFC may interfere with activity of other circuitry responsible for mnemonic or cognitive functions. To investigate this, expression of c-Fos, a marker of neuronal activation, was throughout the brain following PFC GABAA antagonism in the final studies. Reduced PFC GABA function was associated with widespread increases in neuronal activation in PFC efferent regions in animals at rest. Intriguingly, enhanced neuronal activation following PFC disinhibition was only observed in the hippocampus and rhomboid thalamic nucleus of animals trained on the task, suggesting that plasticity in the PFC-thalamic-hippocampal circuit associated with learning may alter the effects of diminished PFC GABA function on neuronal activation. Collectively, the work described identifies component aspects of cognition affected by deficiencies of PFC GABA, and suggests that diminished or dysfunctional PFC GABA signalling could play a role in cognitive deficits observed in neuropsychiatric disorders.

Text

2018-05-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/66185

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/