Glutamate Synapses in Human Cognitive Disorders

Abstract

Accumulating data, including those from large genetic association studies, indicate that alterations in glutamatergic synapse structure and function represent a common underlying pathology in many symptomatically distinct cognitive disorders. In this review, we discuss evidence from human genetic studies and data from animal models supporting a role for aberrant glutamatergic synapse function in the etiology of intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ), neurodevelopmental disorders that comprise a significant proportion of human cognitive disease and exact a substantial financial and social burden. The varied manifestations of impaired perceptual processing, executive function, social interaction, communication, and/or intellectual ability in ID, ASD, and SCZ appear to emerge from altered neural microstructure, function, and/or wiring rather than gross changes in neuron number or morphology. Here, we review evidence that these disorders may share a common underlying neuropathy: altered excitatory synapse function. We focus on the most promising candidate genes affecting glutamatergic synapse function, highlighting the likely disease-relevant functional consequences of each. We first present a brief overview of glutamatergic synapses and then explore the genetic and phenotypic evidence for altered glutamate signaling in ID, ASD, and SCZ.

BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method

“…This finding is supported by a knockout study that established a link between BRaf signaling and long-term potentiation (Chen et al 2006) and is consistent with the earlier reports that BRaf was the sole Raf kinase expressed-and expressed at a high level-at synapses (Morice et al 1999;Husi et al 2000). These findings, which implicate a possible involvement of BRaf in canonical Ras signaling at synapses, underscore the importance of defining the precise synaptic function of BRaf (Nishiyama and Yasuda 2015;Volk et al 2015).…”

“…Rapid advances in genetics have identified large numbers of putative disease-linked mutations on numerous genes (Govek et al 2005;Schubbert et al 2007;Pavlowsky et al 2012;Rauen 2013;Mei and Nave 2014;Siegert et al 2015;Volk et al 2015). However, how the disease-linked genes and mutations may differentially affect cellular functions and behavioral outputs remains poorly understood, primarily due to the time-and cost-prohibitive approaches for generating the large numbers of transgenic animal models required to understand the physiopathology of genes and their mutations (Govek et al 2005;Siegert et al 2015;Volk et al 2015). For example, geneticists have linked ∼40 mutations on the BRaf gene that encodes a serine/threonine protein kinase to cardio-facio-cutaneous syndrome (CFC) (Supplemental Fig.…”

A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function

“…For example, FMRP (Fragile X Mental Retardation Protein) is an RNA-binding protein linked to trafficking and translation of synaptic proteins (48), the TSC1/TSC2 complex is known to regulate mTOR-mediated protein translations (49,50), and Ube3a acts as an E3 ligase to regulate synaptic protein turnover (51). It becomes increasingly obvious, albeit with poorly understood underpinning mechanisms, that mutations of one gene (or one common set of genes) can lead to different psychiatric disorders (52). It is possible that different mutations on one gene (e.g., Shank3 deletion vs. duplication) can directly lead to opposite changes in the expression level of the encoded protein, thereby leading to opposing neuronal activity changes (53).…”

Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior

“…We further detected increased sEPSC amplitude in the Ndrg2 -/-CA1 pyramidal neurons, suggesting that elevated interstitial glutamate levels underlie the enhanced excitation. Excitatory glutamatergic system dysfunction plays an important role in the pathogenesis of neuropsychiatric disorders (58)(59)(60)(61)(62). A few studies have investigated the role of glutamate in the context of ADHD (63,64), although their conclusions are not completely consistent.…”