3. Entraining Neural Networks Through Parvalbumin-Positive Interneurons: Can This Offer a Better way to Treat Schizophrenia?

摘要

>Overall Abstract: Fast-spiking, parvalbumin-positive GABAergic interneurons in corticolimbic neural circuits modulate the synchronous firing of pyramidal neurons to enhance gamma synchrony in support of cognitive function. Multiple lines of evidence support a major role of parvalbumin (PV) interneurons in the pathophysiology of cognitive dysfunction in schizophrenia. Although the number of cortical PV neurons does not appear to be altered in the disease, they do contain lower messenger RNA and protein levels for PV and the GABA-synthesizing enzyme GAD1. New transcriptome profiling data from laser-captured layer 3 PV neurons in the prefrontal cortex identified over 1000 genes that are differentially expressed in schizophrenia, most of which are not altered in layer 3 pyramidal neurons. Some of the alterations in PV neurons are consistent with a state of heightened plasticity, consistent with recent findings of alterations in another plasticity regulator, and the perineuronal nets that surround PV cells. New anatomical findings indicate that PV neurons receive fewer excitatory inputs in schizophrenia and that this reduction might be attributable to altered splicing of ErbB4, which could disrupt the localization of PSD95 to excitatory synapses, selectively in PV neurons.Several targets have been identified that may lead to novel treatments, which aim to enhance PV interneuron function in patients with schizophrenia. For example, a novel small molecule Kv3.1 channel modulator, , is currently in Phase I development. Muscarinic M1 receptor positive allosteric modulators, such as HTL9936, are also in early clinical development and may act, at least in part, through effects on PV interneurons. Other targets, such as Kv9.3, have been identified, but chemistry programs are yet to start.An understanding of the function of these neurons makes it possible to anticipate specific biomarkers and symptoms that should be prominent. For example, reductions in cortical gamma synchrony, overall cortical excitability, and alterations in cognitive function. Results from the Bipolar Schizophrenia Network for Intermediate Phenotypes consortium show that a subclass of patients with schizophrenia can be identified on the basis on electrophysiological biomarkers consistent with a PV interneuron dysfunction. This specific patient population and the associated defining biomarkers are therefore of particular interest for evaluating the efficacy of novel PV-targeted treatments.This symposia brings together new evidence on the nature of PV interneuron alterations in schizophrenia and their function with the latest data on promising pharmacological strategies to correct PV dysfunction. These findings provide new insights into the nature of PV neurons pathology in schizophrenia and into potential new targets for therapeutic interventions. The symposium will consider the implications of these insights for understanding schizophrenia and trial design for treatments to address them.