Toward a developmental neurobiology of autism

Abstract

Autism is a complex, behaviorally defined, developmental brain disorder with an estimated prevalence of 1 in 1,000. It is now clear that autism is not a disease, but a syndrome with a strong genetic component. The etiology of autism is poorly defined both at the cellular and the molecular levels. Based on the fact that seizure activity is frequently associated with autism and that abnormal evoked potentials have been observed in autistic individuals in response to tasks that require attention, several investigators have recently proposed that autism might be caused by an imbalance between excitation and inhibition in key neural systems including the cortex. Despite considerable ongoing effort toward the identification of chromosome regions affected in autism and the characterization of many potential gene candidates, only a few genes have been reproducibly shown to display specific mutations that segregate with autism, likely because of the complex polygenic nature of this syndrome. Among those, several candidate genes have been shown to control the early patterning and/or the late synaptic maturation of specific neuronal subpopulations controlling the balance between excitation and inhibition in the developing cortex and cerebellum. In the present article, we review our current understanding of the developmental mechanisms patterning the balance between excitation and inhibition in the context of the neurobiology of autism.

Vibrotactile adaptation fails to enhance spatial localization in adults with autism

“…If this widely-held presumption is correct, the findings obtained in the present study raise the possibility that local corticocortical functional connectivity in subjects with autism may be substantially abnormal. While a number of findings have demonstrated that long-range functional connectivity in subjects with autism is very different from that present in the general population (for review, see Polleux and Lauder, 2004;Herbert, 2005), it is unlikely that the different observations obtained from subjects with autism and control subjects reported in this study are attributable to differences in long-range corticocortical connections. Instead, the improved tactile spatial localization that accompanies an increase in duration of adapting stimulation most likely would occur as a result of local dynamic corticocortical interactions that operate to improve the contrast of the primary somatosensory cortical response to a repetitive stimulus through lateral inhibition.…”

“…Based on this perspective, the measures of tactile localization performance described in this paper appear to reflect the deficit in short-range parietal corticocortical connectivity identified in subjects with autism by Casanova and colleagues (Casanova et al, 2002(Casanova et al, , 2003. Such changes in connectivity could lead to the imbalance in excitation and inhibition that others have predicted underlies the neocortical hyperexcitability and unstable activity in cortical networks characteristic of autism (Polleux and Lauder, 2004;Rubenstein and Merzenich, 2003).…”

“…For example, some subjects with autism exhibit hyperarousal to natural sensory input, and a decreased ability to select among competing sensory inputs ( . Although many reports acknowledge a widespread neocortical dysfunction in autism, it is less widely recognized that the dysfunction is non-uniform -e.g., the excessive responsivity of primary sensory cortex to peripheral stimulation is accompanied (in the same subject) by abnormally low activation/responsivity in cortical regions devoted to higher-order information processing (Belmonte et Consideration of the above-described observations, together with the relatively recent demonstration that autism is associated with mutation in regions centered around the GABA A -β3 receptor subunit gene, led some researchers (Belmonte et al, 2004;Polleux and Lauder, 2004) to suggest that the neocortical dysfunction in this disorder may be attributable to a deficiency during early development in GABA-mediated synaptic neurotransmission. According to this view, the excessive excitatory neurotransmission within low-order neocortical processing areas that accompanies insufficient GABA-mediated neocortical inhibition leads to the experience-driven abnormalities in neocortical functional connectivity characteristic of autism.…”

Advances in behavioral genetics: mouse models of autism

“…84,136 Candidate genes derived from association or familial linkage studies include multiple genes relevant to synaptic genesis and function, including GABRB3, GLRB (glycine receptor, b), several genes encoding glutamate receptors, and NLGN3 and NLGN4 (neuroligin 3 and 4). 11,137,138 The neuroligin family, in particular, has been found to have an important role in excitatory and inhibitory synaptic contacts. 139,140 Neuroligins, located in the postsynaptic region, function as transsynaptic cell adhesion molecules, connecting with presynaptic b-neurexin or, in some cases, a-neurexin partners.…”

“…Brain-derived neurotrophic factor (BDNF) has been identified as a candidate gene for autism susceptibility. 11,138 BDNF plays a critical role during neurodevelopment, with effects on dendritic growth and spine maturation, synaptogenesis, and neuronal plasticity. [192][193][194] Work with mouse lines characterized by deficient Bdnf has shown that these trophic effects are important for normal serotonergic neurotransmission.…”