Altered hippocampal coding of social information and neural synchrony in autism – SynchrAutism

We use electrophysiological recording in freely moving mice submitted to social behavioral tasks as well as biochemical, molecular and cellular biological techniques.

Using the improved/adapted equipment, single cell and LFP activity of the hippocampus was recorded so far from 6 WT mice during two behavioral conditions (1) the Crawley task and (2) direct interaction with both the same and different sexes of stimulus mouse. The activity pattern of these hippocampal pyramidal cells demonstrated that about two thirds of CA1 pyramidal cells exhibited changes in firings when mice were presented with a congener either passively (during the Crawley task) or actively (during direct interaction) as compared to exploring environment alone, and the remaining third of cells were place cells. These preliminary data indicate that the mouse hippocampal activity highly integrates social information, and recording of these activities from mutant lines is likely to reveal significant information on the way the social information is processed in the hippocampus to explain their behavioral deficits.
Based on our previous study showing that inhibition of ERK pathway rescues social deficits in Scrib1crc/+ mice, we have selected inhibitors of Mnk1 and mTOR, both acting in the dowstream of ERK pathway, as best molecules to be used for in vivo studies. We found that ip injections of 5 or 10 mg/kg of Mnk1 inhibitor (CGP5738) successfully rescued the known deficits. The effects of mTOR inhibition using rapamycin are currently under study. To verify the obtained drug effects are specific to their actions in the hippocampus, we setup intracerebral injection techniques aiming at delivery of drugs into dorsal dendate gyrus/CA3 of the hippocampus. The previous molecules will be tested for their central effects.

It is well established that rodent hippocampal cells respond to animal’s spatial location (place cell), and this robust phenomenon is observed as mice are freely exploring an environment or running on wheels with their head restrained/fixed to a frame. Our preliminary data recorded from WT mice suggest that a majority of the mouse hippocampal cells also respond strongly to social stimuli (congeners). These data suggest that the mouse hippocampus also integrates social information, and this process might be altered in Shank 3 and Scrib1 mice to explain their social behavioral phenotypes.

One collaborative papier in preparation.
No patent deposited

The overall goal of our proposal, called SynchrAutism, is to examine directly the specific and exact contribution of the hippocampus and neural network synchrony to social behavioral changes in autism.

Most mental and neuropsychiatric diseases are characterized by not only severe behavioral disturbances, notably in social behavior and cognition, but also exaggerated vulnerability of the hippocampus, region important for higher order cognitive functions. Autism, complex and heterogeneous neurodevelopmental disorder, represents a typical mental illness with both characteristics.

Because of high genetic component, mouse models replicating mutations of candidate genes of autism constitute an important tool. While studies involving mutant mice have begun to reproduce both social behavioral impairments and hippocampal synaptic dysfunctioning, validating them as pertinent models of human autism is very important since conclusions drawn from these studies remain essentially correlative. Defining the exact role played by the hippocampal synaptic plasticity and integrity in social behaviors, and its functional alteration in autism, will greatly enhance our understanding of the pathophysiology of autism.

The current proposal aims thus to tackle this issue by approaching it from different levels of analyses. At integrated level, we will examine the nature and content of hippocampal representations of social information, by performing electrophysiological recording of single cell activity from the hippocampus tuned to/triggered by social stimuli (conspecifics, pheromones, ultrasonic vocalizations) during social interaction tasks, and by verifying if the activity pattern is modified in autistic mutant mice, to explain directly social behavioral defects. Because autism is also viewed as a “disconnection syndrome” due to developmental defects in neural network connectivity, we will also look at neural synchrony, beyond the hippocampus, among multiple cortical and subcortical regions during resting state (for default functional connectivity) in addition to social behaviors
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At subcellular level, we will complement scarce information on the cellular and molecular mechanisms that underlie social behavior. Two key complexes of the spine, the Shank3 and the Scrib1 complexes, known for their high implication in both spine defects and social behaviors, are of particular interest in our study. We will dissect the molecular composition of these complexes, determine the interaction of different proteins involved and characterize activating/inhibiting agents to understand their roles in social behavioral impairments in autism.

The findings from our project will provide a novel conceptual framework in the study of autism, that will lead to a better comprehension of altered neurobiological bases of social behaviors in autism, and thus to new therapeutic targets against this devastating mental dysfunction.