Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders

Abstract

Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.

Fig. 1

Simplified architecture of excitatory and inhibitory synapses on pyramidal cells. Pre-synaptic terminals of excitatory synapses release glutamate neurotransmitters that are post-synaptically received by glutamate receptors (NMDARs and AMPARs) on dendritic spines - small membranous protrusion stemming from the dendrite. The tip of each spine contains an electrodense region called the PSD, which is comprised of cytoskeleton anchoring proteins, such as PSD-95, designed to scaffold glutamate receptors (NMDARs and AMPARs) to the spine’s surface and to dock hundreds of signaling molecules (not shown) to the underside. Inhibitory synapses are localized to the dendritic shaft. Pre-synaptic terminals release GABA to be received post-synaptically by GABARs anchored onto the post-synaptic surface by gephyrins (gephyrins also scaffold glycine receptors, which are activated by glycine neurotransmitters - not shown). Noticeably missing is the PSD. Both synapse types are structurally maintained by trans-synaptic adhesions through cell adhesion molecules.

Fig. 2

Parvalbumin-containing interneurons regulate pyramidal cell firing. Both basket (green) and chandelier cells neurons (red) contain parvalbumin and have fast-spiking electrophysiological properties. Chandelier cells have long linear axon terminals called cartridges that synapse onto the axon initial segment of pyramidal neurons (black) while basket cell axons target the cell bodies and proximal dendrites of pyramidal neurons. Due to the strategic location of their synapses, both subtypes greatly influence the generation and timing of a pyramidal cell’s action potentials. The contents inside the blue and orange boxes respectively denote key SCZ and ASD-associated genes involved with dendritic spine or parvalbumin interneuron pathology, as discussed in this review.