Abnormal Fear Conditioning and Amygdala Processing in an Animal Model of Autism

Abstract

A core feature of autism spectrum disorders is the impairment in social interactions. Among other brain regions, a deficit in amygdala processing has been suggested to underlie this impairment, but whether the amygdala is processing fear abnormally in autism, is yet not clear. We used the valproic acid (VPA) rat model of autism to (a) screen for autism-like symptoms in rats, (b) test for alterations in amygdala-dependent fear processing, and (c) evaluate neuronal reactivity and synaptic plasticity in the lateral amygdala by means of in vitro single-cell electrophysiological recordings. VPA-treated animals displayed several symptoms common to autism, among them impaired social interactions and increased repetitive behaviors. Furthermore, VPA-treated rats were more anxious and exhibited abnormally high and longer lasting fear memories, which were overgeneralized and harder to extinguish. On the cellular level, the amygdala was hyperreactive to electrical stimulation and displayed boosted synaptic plasticity as well as a deficit in inhibition. We show for the first time enhanced, overgeneralized and resistant conditioned fear memories in an animal model of autism. Such hyperfear could be caused by the hyperreactivity and hyperplasticity found in the lateral amygdala, which may in turn be due to a deficit in the inhibitory system of the amygdala. We hypothesize an 'aversive world' syndrome that could, even if not a primary cause of the disorder itself, underlie some core symptoms in autism, such as impairments in social interactions and resistance to rehabilitation.

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

“…Our results are also broadly consistent with observations by Markram and colleagues, who found that VPA-treated rats exhibited abnormally high and longer lasting fear memories [67]. However, since that team did not explore the relationship between CS and context conditioning, and we did not examine fear memories over a longer period, it is difficult to directly compare our 2 studies [67].…”

“…Although PPI deficits have been reported in higher functioning adults with ASD [68] or Asperger"s Disorder [69], equivocal PPI findings have been reported in lower functioning children and adolescents [70] and in a cohort of individuals with both high-and low functioning individuals with ASD [71]. A higher dose of VPA in late gestation has been reported to alter PPI [67], however other late gestation exposures which may increase risk of ASD -specifically maternal immune activation -do not disrupt PPI either [28][29][30]. Thus, a PPI impairment is not always a consequence of exposure to ASD risks.…”

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder

“…Recall of the platform position was also poor in the 72 hour post-training probe trial during which the VPA-treated animals spent less than 20% of time in the target quadrant ( Figure 5B). It should be noted, however, that previous studies employing the VPA model of autism have failed to detect any deficits in rat spatial learning (Markram et al, 2008).…”

Synaptic and Intrinsic Balancing during Postnatal Development in Rat Pups Exposed to Valproic Acidin Utero

“…Young VPA rats (ϳP14) have been the subject of an extensive and impressive series of physiological experiments (Rinaldi et al, , 2008aMarkram et al, 2008). These have identified abnormalities in neuronal excitability, synaptic transmission and connectivity, and synaptic plasticity.…”