Synaptic microcircuit dysfunction in genetic models of neurodevelopmental disorders: focus on Mecp2 and Met

Recent findings in the genetics of neurodevelopmental syndromes have ushered in an exciting era of discovery in which substrates of neurologic dysfunction are being identified at the synaptic and microcircuit levels in mouse models of these disorders. We review recent progress in this area, focusing on two examples of mouse models of autism spectrum disorders (ASDs): Mecp2 models of Rett syndrome, and a Met-knockout model of non-syndromic forms of autism. In both cases, a dominant theme is changes in synaptic strength, associated with hyper-connectivity or hypo-connectivity in specific microcircuits. Alterations in intrinsic neuronal excitability are also found, but do not appear to be as common. The microcircuit-specific nature of synaptic changes observed in these ASD models indicates that it will be necessary to define mechanisms of circuit dysfunction on a case-by-case basis, not only in neocortex but also in brainstem and other sub-cortical areas. Thus, functional microcircuit analysis is emerging as an important line of investigation, highly complementary to neurogenetic and molecular strategies, and holds promise for generating models of the underlying pathophysiology and for guiding development of novel therapeutic strategies.

► Identifies emerging themes of microcircuit dysfunction in autism spectrum disorders. ► Compares and contrasts Mecp2 and Met mouse models of ASDs. ► Changes occur more often in synaptic strength than in intrinsic neuronal excitability. ► Microcircuit changes, for example hyper-connectivity versus hypo-connectivity, are cell-context specific. ► Distinguishing core defects versus compensatory changes is a high priority.