**16. Current GABA‐targeted therapeutics**

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 presynaptically and GABAAα2 receptors are increased postsynaptically. These changes result in levels of GABA remaining in the synaptic cleft longer and more postsynaptic receptors available for activation. GABA Aα2 receptor agonists offer as a promising therapeutic to phar‐ macologically target the pathophysiological inhibitory deficit in the DLPFC [62]. GABAAα2 receptors are predominately located at the axon initial segment of pyramidal neurons and therefore should exhibit limited off‐target effects on other domains [83]. GABAAα2 ‐selective benzodiazepines are a likely candidate because these agents would only activate and poten‐ tiate GABAAα2 receptors in the presence of GABA, preventing dysregulated inhibition that 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, due to the anxiolytic effects that are mediated by GABAAα2 receptors [62, 84]. In aims to provide better treatment options, further research is warranted to elucidate the underlying mechanism of GABAergic hypofunctioning, which largely contribute to working memory deficits seen in schizophrenia.

## **17. Summary**

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.
