THE EFFECTS OF AUTISM-ASSOCIATED TBR1 HAPLOINSUFFICIENCY ON AMYGDALA MORPHOLOGICAL AND FUNCTIONAL CONNECTIVITY

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that effects about 1 in 44 children and has steadily increased in prevalence over the last decades. ASD is characterized by the diagnostic criteria of a persistent deficit in social communication and interaction and restricted or repetitive behaviors. The amygdala plays an essential role in regulating these behaviors and has continuously been shown to be affected in patients with ASD. As the amygdala is connected throughout the brain with cortical and subcortical areas, it is crucial to understand potential circuit impairments that contribute to the development and progression of behavioral characteristics. In this study, we investigated the role of ASD-associated TBR1 haploinsufficiency on morphological and functional amygdala connectivity. While we don’t see differences in inputs to the basal amygdala (BA), we demonstrated a difference in the BA to prefrontal cortex (PFC) pathway. Interestingly, we show a specific innervation difference of layer 5 neurons in the infralimbic (IL) but not prelimbic (PL) nuclei in the PFC. In accordance with the overall reduced density of BA axons in the IL, we show a decreased density of excitatory synapses. To investigate possible functional consequences of this projection deficit, we characterized pre-and postsynaptic functions of BA-PFC synapses. TBR1 haploinsufficiency impairs the postsynaptic function of BA-PL layer 2/3 and IL layer 5 synapses. BA-PL layer 2/3 synapses show an increased AMPA/NMDA receptor ratio, while this is not observed in BA-IL layer 5 synapses. However, TBR1 haploinsufficiency increases the AMPA and NMDA receptor-mediated currents at these synapses, further highlighting that BA-PL and BA-IL synapses are different and that partial loss of TBR1 affects circuits differently. This novel characterization of the consequences of a TBR1 haploinsufficiency on BA connectivity contributes to the critical understanding of this ASD-associated gene and its detrimental effects that contribute to the underlying behavioral phenotype.