Exploring distributed neural network connections in a rat model of SYNGAP1 haploinsufficiency

Abstract

Neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), intellectual disability (ID), and childhood epilepsy, have been attributed to SYNGAP1 haploinsufficiency – a genetic condition characterized by alterations in the SYNGAP1 gene. This gene plays a pivotal role in the proper development and functioning of neural circuits associated with cognitive processes and emotional responses. Fear conditioning, a vital aspect of adaptive behaviour, involves learning to associate specific stimuli with threat and is a fundamental model for exploring the neural basis of fear memory.

This study explores the behavioural and neural manifestations of fear conditioning in wildtype (WT) and Syngap+/∆GAP (SG) rats. Fear extinction, a process where learned fear responses diminish when the conditioned stimulus (CS) no longer predicts the unconditioned stimulus (US), was investigated in both genotypes. As with previous laboratory findings, SG rats exhibited sustained freezing behaviour during extinction, indicative of difficulty in unlearning the CS-US association compared to their WT counterparts.

To investigate the neural basis of these differences, we employed in vivo electrophysiological techniques combined with sophisticated neural data analysis. While rats underwent surgical procedures to implant six local field potential (LFP) and three electroencephalogram (EEG) electrodes across relevant brain structures, our analysis focuses on key brain regions including the infralimbic cortex, amygdala, and olfactory bulb – regions implicated in fear memory and extinction. To extract insights from data, a custom software analysis package was developed in MATLAB, and power and coherence analyses were conducted to identify potential electrophysiological biomarkers that differentiate the genotypes and predict their variations in behaviour.

While no definitive biomarkers for freezing behaviour emerged, intriguing patterns requiring further investigation surfaced in the gamma and delta frequency bands across multiple brain regions. Notably, the olfactory bulb’s power showed a significant correlation with prolonged freezing, suggesting a potential neural driver or result of this behaviour. These findings emphasize the complex interplay between neural circuits and behaviour, indicating that SG rats might possess an elevated baseline anxiety level compared to WT rats, possibly contributing to their propensity for freezing.

In summary, this thesis explores the connection between SYNGAP1 haploinsufficiency and fear-related behaviours. By employing fear conditioning as a model, we reveal how altered neural dynamics in SG rats could underlie their impaired fear extinction. Understanding these mechanisms not only advances our knowledge of NDDs but also provides insights into the broader mechanisms governing fear learning and memory.