**15. Parvalbumin interneuronal hypofunctioning in schizophrenia**

Schizophrenia is a debilitating neurodevelopmental disorder in which afflicted individu‐ als suffer from cognitive impairments, working memory deficits being a core feature. Unfortunately, available medications poorly treat cognitive symptoms albeit cognitive performance most strongly determines functional outcomes. Working memory function requires fast and synchronous inhibition of pyramidal neuronal networks within the pre‐ frontal cortex, which is regulated by GABAergic neurotransmission. Because individuals afflicted with schizophrenia display reduced frontal cortical gamma oscillatory power in the DLPFC during a working memory task and cognitive impairments are a core feature, dis‐ rupted GABAergic signaling is highly implicated in the pathology of this disorder [57, 62]. Glutamic acid decarboxylase (GAD), the enzyme that synthesizes GABA and PV prefrontal expression is reduced in schizophrenia, further demonstrating a GABA deficit in this neuro‐ anatomical region [57, 62, 77–79].

NMDARs have been demonstrated to be vital throughout neurodevelopment, with NR2A specifically involved in the maturation and maintenance of GABAergic PV interneurons. A previous study showed that NR2A hypofunction leads to reduced GAD67 expression and PV immunoreactivity [59]. It is important to note that the reduction in parvalbumin is not due to density (i.e., interneuronal cell number), but rather a decrease in protein level expression. Researchers hypothesized that this suppressed expression in GAD67, and therefore PV, leads to GABAergic malfunctioning or hypofunctioning [57, 59, 62, 77]. Interestingly, GAD65, the other isoform, does not demonstrate such impairments. Cortical levels of GABA remained unaltered in animals without GAD65, thus demonstrated specificity to the GAD67 isoform [57, 62, 80]. Reductions in GAD67, however, are associated with decreased GAD enzymatic activity as well as GABA levels in the cortex [62, 81]. Individuals suffering from schizophrenia were also reported to have increases in the α2 subunit of GABAA receptors and decreased GABA trans‐ porter 1 (GAT1) levels. GAT1 are proteins important for the removal of GABA from the synaptic cleft, while the GABAA α2 subunit is highly concentrated at the axon initial segment of pyrami‐ dal neurons and mediate fast synaptic inhibitory neurotransmission (**Figure 9**). Therefore, this

example of single unit prefrontal Delay cell activity in the primate dorsolateral prefrontal cortex (DLPFC) during an oculomotor delayed‐response task. In this working memory task, subjects are trained to fix their gaze at the center. A single cue is presented somewhere in the 360° perimeter, followed by a brief delay period in which the cue is absent. After the delay period, an appropriate response would be an eye saccade in the direction that the cue was

Working memory, the sustained neuronal activity that occurs during the delay, is not only dependent on prefrontal pyramidal cells, but also fast‐spiking GABAergic interneurons [57, 62, 71]. Pharmacological evidence supports the importance of fast‐spiking interneu‐ rons in the DLPFC for working memory function. Administration of a GABAAR antagonist, bicuculline, lead to impaired mnemonic tuning during an oculomotor delayed‐response task. Therefore, working memory, particularly sustained neuronal activity during the delay period, depends on GABAA receptors. Furthermore, GABAergic hypofunctioning in the DLPFC partly contributes to working memory deficits [62, 75]. GABAergic neuro‐ nal activity and its role in working memory function are also connected to gamma oscilla‐ tions. Gamma oscillations, which fall in the band range between 30 and 60 Hz, are required for working memory function. A research study conducted in 2003 reported that gamma band oscillations increased proportionally with working memory load [57, 62, 76]. More specifically, fast‐spiking PV interneurons are a crucial input for gamma rhythm genera‐ tion. Inhibition of PV interneurons attenuates gamma oscillations, whereas driving PV neuronal activity initiates gamma‐frequency rhythms [62]. Excitatory pyramidal output in the prefrontal cortex is modulated by inhibitory gamma oscillations, largely driven my PV‐ interneurons, essentially fine‐tuning the circuit and allowing for proper working memory function. Conclusively, PFC‐dependent working memory involves a symbiotic balance between excitatory pyramidal output and fast inhibitory activity of PV‐interneurons, which

**15. Parvalbumin interneuronal hypofunctioning in schizophrenia**

Schizophrenia is a debilitating neurodevelopmental disorder in which afflicted individu‐ als suffer from cognitive impairments, working memory deficits being a core feature. Unfortunately, available medications poorly treat cognitive symptoms albeit cognitive performance most strongly determines functional outcomes. Working memory function requires fast and synchronous inhibition of pyramidal neuronal networks within the pre‐ frontal cortex, which is regulated by GABAergic neurotransmission. Because individuals afflicted with schizophrenia display reduced frontal cortical gamma oscillatory power in the DLPFC during a working memory task and cognitive impairments are a core feature, dis‐ rupted GABAergic signaling is highly implicated in the pathology of this disorder [57, 62]. Glutamic acid decarboxylase (GAD), the enzyme that synthesizes GABA and PV prefrontal expression is reduced in schizophrenia, further demonstrating a GABA deficit in this neuro‐

first presented.

16 Schizophrenia Treatment - The New Facets

shapes and fine‐tunes the circuit.

anatomical region [57, 62, 77–79].

**Figure 9.** Comparison of normal and schizophrenia synaptic connection at the junction between a parvalbumin chandelier interneuron (PVCh) and a pyramidal axon initial segment. A core feature of schizophrenia is GABergic deficits; in the rebalanced circuitry, presynaptic expression of GABA transporter 1 (GAT1) on the axonal terminals of the GABAergic interneurons is decreased, while the expression of GABAAα2 receptors at the axon initial segments of pyramidal neurons is increased (Modified from Lewis et al. [62] and Lewis et al. [57]).

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 root of these dysfunctions.
