Impaired perception and production of language, as well as deficits in social behavior generally, are pervasive features among the autism spectrum disorders (ASD). However, the changes to in vivo circuitry that connect disordered molecular and developmental events to altered behavior are largely unknown. Therefore, the goals of this proposal are: 1) To identify inhibitory neuronal circuits that support vocal perception 2) To determine how they are impaired in a rodent model of Rett syndrome 3) To repair the inhibitory circuitry using novel genetic and pharmacological strategies. To achieve these goals, we propose to use a combination of novel behavioral assays, genetic methods, and electrophysiology. With these tools, we can observe plasticity in specific inhibitory circuits, assess the neural and behavioral consequences of perturbing these circuits, and ultimately restore behavioral function by repairing those circuits. In our preliminary data, we describe a simple, robust and ethologically relevant assay of maternal behavior in a model of Rett syndrome (mice carrying only one copy of the gene MeCP2 - `hets'). Our results with this assay reveal a profound deficit of maternal social learning in hets that we hypothesize is related to poor perception of pup vocalizations. Indeed, we link gathering behavior to function and plasticity of the auditory cortex by showing that: 1) MeCP2 expression in the auditory cortex is necessary for proficient maternal behavior. 2) Auditory cortical neurons in hets exhibit impaired plasticity of inhibitory responses to vocal stimuli. 3) Immunohistochemical marker data reflect dysregulated maturation of auditory cortical inhibitory networks in response to maternal experience. Crucially, the hets are characterized by enhanced expression of perineuronal nets (PNNs), structures that closely associate with inhibitory networks and are thought to limit plasticity. 4) A `genetic rescue' manipulation of GABAergic inhibitory function relieves the elevated PNN expression, and remarkably restores normal behavioral performance. 5) Pharmacological inhibition of PNNs selectively in the auditory cortex prior to maternal experience is sufficient to restore maternal learning as well. Our objectives are to identify specific auditory cortical circuits governing vocal perception, to determine the in vivo functional consequences of MeCP2 heterozygosity in these circuits, and to rescue circuit function and behavior with a genetic manipulation of these circuits. By achieving these goals, we will forge crucial links between molecular and circuit pathologies and impaired social communication in the Rett syndrome mouse model, and we will potentially identify candidate circuit targets for therapeutic intervention.
The goal of this project is to use mouse models to identify some of the neural circuit pathologies that underlie communication deficits in Rett syndrome. Successful completion of the aims will make important advances in our understanding of the contribution of inhibitory/excitatory balance to autism spectrum disorders generally, and will likely indicate specific neural circuits that could be targeted for novel therapies.
|Krishnan, Keerthi; Lau, Billy Y B; Ewall, Gabrielle et al. (2017) MECP2 regulates cortical plasticity underlying a learned behaviour in adult female mice. Nat Commun 8:14077|