Neural circuits of inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) are functionally altered in schizophrenia (SZ). Furthermore, it appears that glutamatergic neurotransmission on PV neurons via the N-methyl-D-aspartate (NMDA) receptor in the prefrontal cortex (PFC) may be deficient in SZ. In this application, we will examine whether other glutamate receptor subunits, including the AMPA (1-amino- 3-hydroxyl-5-methyl-4-isoxazole-propionate) GluR2 subunit and the metabotropic group I glutamate receptor mGluR1 or 5 subunit, or the dopamine D1 receptor may contribute to NMDA neurotransmission deficiency. Deficient NMDA neurotransmission on PV neurons may further contribute to PV neuronal dysfunction via at least two mechanisms: oxidative stress and decreased expression of voltage-gated potassium channels Kv3.1b and Kv3.2, which play a critical role in conferring the fast-spiking properties to PV neurons. Hence, we will use immunoblot technique to examine two enzymes that promote oxidative stress, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) and neuronal nitric oxide synthase (nNOS), and the catalytic and modulatory subunits of the antioxidant enzyme glutamate cysteine ligase in homogenized PFC. We will also examine the expression of the mRNA for interleukin 6, which activates Nox production and thus promote oxidative stress, in PV neurons. In addition, we will measure the mRNA for Kv3.1b and Kv3.2 in PV neurons to see if they may be decreased in SZ. Because PV neurons are ensheathed by chondroitin sulfate proteoglycans-rich perineuronal nets (PNNs), which are thought to play a crucial role in maintaining their functional integrity, we will examine whether the number of PNNs may be decreased in SZ. Finally, it is postulated that deficits of PV neurons during the peri-adolescent period may derail the trajectories of cortical maturation, contributing to the onset of SZ. We will explore the transcriptional regulation of PV neuronal circuits both in SZ and during normal peri-adolescent human PFC development in order to gain insight into the possible molecular mechanisms of SZ onset. Taken together, findings from the proposed experiments will improve our understanding of the pathophysiology of SZ and the molecular mechanisms that may contribute to its onset. As such, they may lead to the conceptualization of treatment and prevention strategies that aim at fundamentally correcting or recalibrating the dysfunctional PV neuronal circuits.
The goal of this application is to improve our understanding of the molecular mechanisms that mediate the disturbances of inhibitory neural circuits in schizophrenia. Findings of the proposed studies are expected to shed light on the conceptualization of treatment and prevention strategies that aim at fundamentally correcting the underlying neural circuit deficits.
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