Sensory processing in autism spectrum disorders and Fragile X syndrome—From the clinic to animal models

Abstract

Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and in relevant rodent models. This includes electroencephalographic measurement of event related potentials, neural oscillations and mismatch negativity, as well as habituation and pre-pulse inhibition of startle. We outline robust evidence of disrupted sensory processing in individuals with ASD and FXS, and in respective animal models, focusing on the auditory sensory domain. Animal models provide an excellent opportunity to examine common mechanisms of sensory pathophysiology in order to develop therapeutics.

BK Channels Mediate Synaptic Plasticity Underlying Habituation in Rats

“…Electrophysiological experiments were performed as reported previously (Bosch andSchmid, 2006, 2008;Simons-Weidenmaier et al, 2006;Geis and Schmid, 2011). Evoked EPSCs (eEPSCs) were recorded in PnC neurons in whole-cell voltage-clamp at room temperature while continuously perfused with ACSF (1-2 ml/min), containing 50 M picrotoxin.…”

“…We have previously proposed that short-term habituation of acoustic startle is mediated by activity-dependent synaptic depression of these glutamatergic synapses in the PnC, induced by "bursts" (i.e., short trains of four or more action potentials at 100 -150 Hz), which mimics their activity pattern during startle in vivo (Weber et al, 2002;Simons-Weidenmaier et al, 2006). To test whether BK channels play a functional role in the activitydependent depression of these synapses, we induced synaptic depression under different experimental conditions as described previously (Weber et al, 2002;Simons-Weidenmaier et al, 2006;Schmid et al, 2010).…”

“…Habituation, especially short-term habituation of escape responses and protective reflexes, has been studied extensively in different animal models ranging from Caenorhabditis elegans, Aplysia, Drosophila, and other invertebrates to rats, monkeys, and humans. Its neural basis seems to lie in a depression of synaptic transmission within the respective sensorimotor pathway (Simons-Weidenmaier et al, 2006;for review, see Glanzman, 2009); however, the underlying molecular mechanism is still not well understood. In mammals, habituation also represents an important sensory filter that reduces the load of sensory information processed by higher brain areas.…”

“…Several psychiatric disorders, most prominently schizophrenia and autism, are associated with impairments in ASR habituation (Braff et al, 1992;Ornitz et al, 1993;Perry et al, 2007). In people with autism spectrum disorder (ASD) disrupted habituation is accompanied with hypersensitivity or hyposensitivity to sensory stimuli, which has a debilitating impact on social interactions and daily functioning (Hirstein et al, 2001;Minshew et al, 2002;Zwaigenbaum et al, 2005;Leekam et al, 2007;Crane et al, 2009;Schoen et al, 2009;Elison et al, 2013;Elsabbagh et al, 2013;Stroganova et al, 2013;for review, see Sinclair et al, 2016).…”

“…It has been proposed that short-term habituation of startle occurs in the afferent sensory part of startle pathway (Davis and Gendelman, 1977;Davis et al, 1982a, b;Simons-Weidenmaier et al, 2006), specifically through presynaptic depression of auditory afferent synapses on sensorimotor neurons of caudal pontine reticular nucleus (PnC) in the brainstem (Leitner et al, 1980;Lingenhöhl and Friauf, 1992;Weber et al, 2002;Simons-Weidenmaier et al, 2006). BK channels are densely expressed in synaptic terminals in cerebral cortex, hippocampus, hypothalamus, brainstem, and spinal cord (Tseng-Crank et al, 1994;Sausbier et al, 2006). BK channels are activated in response to Ca 2ϩ influx and membrane depolarization (Lancaster and Adams, 1986;Lang and Ritchie, 1987).…”