Abnormal fear conditioning and amygdala processing in an animal model of autism.
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.
Markram
Kamila
K
Brain Mind Institute, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. kamila.markram@epfl.ch
Rinaldi
Tania
T
La Mendola
Deborah
D
Sandi
Carmen
C
Markram
Henry
H
D000679:Amygdala / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology; D001321:Autistic Disorder / Q000473:pathology* / Q000523:psychology; D001522:Behavior, Animal; D003213:Conditioning, Psychological / Q000502:physiology*; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D005239:Fear / Q000502:physiology / Q000523:psychology*; D005260:Female; D007398:Interpersonal Relations; D017774:Long-Term Potentiation / Q000502:physiology / Q000528:radiation effects; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D014635:Valproic Acid