**Acknowledgements**

inverse correlation is speculated to act as a compensatory mechanism to increase the effect of GABA on postsynaptic cells and return the circuitry back to homeostatic conditions [57, 62, 82]. However, what remains to be unanswered is which proceeds which: NMDA receptor hypo‐ functioning or GABAergic deficits. In order to understand how cognitive impairments in schizophrenia emerge, we must first uncover the molecular underpinnings that lead to the

In individuals afflicted with schizophrenia, a compensatory mechanism to balance the circuit naturally gets set into motion. In order to offset the shift towards excitation, GAT1 is reduced

in levels of GABA remaining in the synaptic cleft longer and more postsynaptic receptors

macologically target the pathophysiological inhibitory deficit in the DLPFC [62]. GABAAα2 receptors are predominately located at the axon initial segment of pyramidal neurons and

benzodiazepines are a likely candidate because these agents would only activate and poten‐

would otherwise result from direct activation of these receptors. Treatment with GABAAα2‐ selective benzodiazepines might also offer an additive benefit of reducing anxiety in patients,

provide better treatment options, further research is warranted to elucidate the underlying mechanism of GABAergic hypofunctioning, which largely contribute to working memory

Working memory is a key executive function that guides an organism's response by filter‐ ing out important information from the external environment and applying relevant details towards a goal‐directed behavior. This process requires the output of a specialized circuit localized within the prefrontal cortical circuits. The synchrony between excitatory pyrami‐ dal Delay cells, which produce the necessary persistent neuronal activity, and fast‐spiking GABAergic neurotransmission, which in turn shape and fine‐tunes the pyramidal cell out‐ put, underlies working memory. Both the excitatory and inhibitory components (such as NMDARs and GABAARs) are crucial in the maintenance of this delicate process, and dys‐ regulation of either likely serves as a pathophysiological process in schizophrenia. Working memory deficits are a core feature of schizophrenia with NMDA and GABA hypofunctioning highly implicated in the etiology of the disease. Future research is warranted for further deci‐

phering whether NMDA hypofunctioning precedes GABAergic deficits or vice versa.

receptors in the presence of GABA, preventing dysregulated inhibition that

therefore should exhibit limited off‐target effects on other domains [83]. GABAAα2

due to the anxiolytic effects that are mediated by GABAAα2

receptors are increased postsynaptically. These changes result

receptor agonists offer as a promising therapeutic to phar‐

‐selective

receptors [62, 84]. In aims to

root of these dysfunctions.

18 Schizophrenia Treatment - The New Facets

presynaptically and GABAAα2

deficits seen in schizophrenia.

tiate GABAAα2

**17. Summary**

available for activation. GABA Aα2

**16. Current GABA‐targeted therapeutics**

This work was supported by NIH R01MH085666, R21MH110678, and NARSAR Independent Investigator Award 2016 from the Brain and Behavior Research Foundation to W.J. Gao.
