Alterations of GABAergic signaling in autism spectrum disorders

Abstract

Autism spectrum disorders (ASDs) comprise a heterogeneous group of pathological conditions, mainly of genetic origin, characterized by stereotyped behavior, marked impairment in verbal and nonverbal communication, social skills, and cognition. Interestingly, in a small number of cases, ASDs are associated with single mutations in genes encoding for neuroligin-neurexin families. These are adhesion molecules which, by regulating transsynaptic signaling, contribute to maintain a proper excitatory/inhibitory (E/I) balance at the network level. Furthermore, GABA, the main inhibitory neurotransmitter in adult life, at late embryonic/early postnatal stages has been shown to depolarize and excite targeted cell through an outwardly directed flux of chloride. The depolarizing action of GABA and associated calcium influx regulate a variety of developmental processes from cell migration and differentiation to synapse formation. Here, we summarize recent data concerning the functional role of GABA in building up and refining neuronal circuits early in development and the molecular mechanisms regulating the E/I balance. A dysfunction of the GABAergic signaling early in development leads to a severe E/I unbalance in neuronal circuits, a condition that may account for some of the behavioral deficits observed in ASD patients.

Figure 1

Patterns of electrical activity observed at late embryonic/early postnatal stages in the cortex. E20: uncorrelated calcium spikes; P0: Spontaneous Plateau Assemblies (SPAs) synchronized by gap junctions. P3–P5: early network oscillations (ENOs) mediated by glutamate. P6–P8: giant depolarizing potentials (GDPs) mediated by GABA and glutamate. (Modified from [32]).

Figure 2

Pairing GABA-mediated GDPs with Schaffer collateral stimulation persistently enhances synaptic strength at glutamatergic CA3-CA1 connections. (a) Experimental paradigm. (b) The rising phase of GDPs (between the dashed lines) was used to trigger synaptic stimulation (stim) (c) EPSCs evoked in CA1 principal cells by minimal stimulation of Schaffer collateral, before and after pairing (average of 19 responses). (d) Each bar represents the mean peak amplitude of synaptic responses including failures (n = 8) and the paired pulse ratio (PPR; n = 8), obtained before (open) and after (closed) pairing. (Modified from [50]).

Figure 3

Structural organization of GABAergic synapses. The postsynaptic organization comprises a large number of proteins that allow the correct targeting, clustering and stabilization of GABA_A receptors. Among them gephyrin forms hexagonal lattices that trap GABA_A receptors in precise apposition to presynaptic release sites. Cell adhesion molecules of the neuroligin-neurexin families bridge the cleft and ensure transsynaptic signaling, essential for the maintenance of a proper E/I balance.