Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models

Abstract

Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. The affected genes often encode synaptic components directly, but also include regulators that secondarily mediate the synthesis or assembly of synaptic proteins. The prime example is Fragile X syndrome (FXS), the leading heritable cause of both intellectual disability and autism spectrum disorders. FXS results from loss of mRNA-binding FMRP, which regulates synaptic transcript trafficking, stability and translation in activity-dependent synaptogenesis and plasticity mechanisms. Genetic models of FXS exhibit striking excitatory and inhibitory synapse imbalance, associated with impaired cognitive and social interaction behaviors. Downstream of translation control, a number of specific synaptic proteins regulate excitatory versus inhibitory synaptogenesis, independently or combinatorially, and loss of these proteins is also linked to disrupted neurodevelopment. The current effort is to define the cascade of events linking transcription, translation and the role of specific synaptic proteins in the maintenance of excitatory versus inhibitory synapses during neural circuit formation. This focus includes mechanisms that fine-tune excitation and inhibition during the refinement of functional synaptic circuits, and later modulate this balance throughout life. The use of powerful new genetic models has begun to shed light on the mechanistic bases of excitation/inhibition imbalance for a range of neurodevelopmental disease states.

Increased power of resting-state gamma oscillations in autism spectrum disorder detected by routine electroencephalography

“…Ongoing neural activity can be assessed noninvasively during a resting-state EEG recording, i.e., in the absence of task performance or sensory stimulation, in which patterns of neural oscillations may be detected [2]. It has been suggested that elevated oscillatory activity in ASD might indicate hyperactivity in cortical circuits, and subsequently may be associated with the ''autistic'' state [3,4], which is in agreement with a recent review summarizing EEG abnormalities during resting-state paradigms in ASD, reporting increased power in low (delta, theta) and high frequencies (beta, gamma) and reduced activity in middlerange frequencies (alpha) [2]. A few experimental studies report altered resting-state gamma activity by EEG or MEG.…”

Avances en investigación de la discapacidad intelectual de origen genético: tratamientos experimentales en el síndrome X frágil

“…Esto provoca modificaciones en el número y madurez de las espinas dendríticas que conllevan una alteración en la funcionalidad a nivel de la sinapsis neuronal, con desequilibrio entre la excitación y la inhibición por desaparición o sobreexpresión de receptores de Glutamato y/o de GABA (Gatto y Broadie, 2010). Estas alteraciones determinarán el fenotipo conductual de los pacientes con SXF.…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…These inhibitory synapses besides their distinct location are also structurally different compared to excitatory synapses (reviewed in Gatto and Broadie, 2010).…”

“…Immunostaining can be employed with specific antibodies that recognize vesicular glutamate transporters (VGLUTs) and the postsynaptic density protein-95 kDa (PSD-95) that are characteristic of excitatory synapses, while inhibitory synapses are identified by the presence of the vesicular GABA (VGAT) and vesicular inhibitory amino acid (VIAAT) transporters and the postsynaptic adaptor protein gephryin (Gatto and Broadie, 2010). There are commercial available synaptogenesis assay kits that rely on the immunostaining of cells with MAP-2, PSD-95 and synaptophysin.…”