Abstract Autism is a neurodevelopmental disorder characterized by social difficulties, impaired communication skills and repetitive behavioral patterns. Additionally, there is evidence that auditory ...deficits are a common feature of the autism spectrum disorders. Despite the prevalence of autism, the neurobiology of this disorder is poorly understood. However, abnormalities in neuronal morphology, cell number and connectivity have been described throughout the autistic brain. Indeed, we have demonstrated significant dysmorphology in the superior olivary complex (SOC), a collection of auditory brainstem nuclei, in the autistic brain. Prenatal exposure to valproic acid (VPA) in humans has been associated with autism and in rodents prenatal VPA exposure produces many neuroanatomical and behavioral deficits associated with autism. Thus, in an effort to devise an animal model of the autistic auditory brainstem, we have investigated neuronal number and morphology in animals prenatally exposed to valproic acid (VPA). In VPA exposed rats, we find significantly fewer neurons and significant alterations in neuronal morphology. Thus, prenatal VPA exposure in rats appears to produce similar dysmorphology as we have reported in the autistic human brain.
Abstract Autistic spectrum disorders (ASD) comprise a continuum of psychosocial disorders clinically characterized by social difficulties, impaired communication skills and repetitive behavioral ...patterns. Despite the prevalence of ASD, the neurobiology of this disorder is poorly understood. However, abnormalities in neuronal morphology, cell number and connectivity have been described throughout the autistic brain. Further, there is ample evidence that auditory dysfunction is a common feature of autism. Our preliminary investigation of neuronal morphology in the auditory brainstem of individuals with ASD focused on the medial superior olive (MSO) and revealed that neurons in this region were significantly smaller and rounder than in controls. In this report, we expand our investigation to examine all nuclei within the human superior olivary complex (SOC), an important auditory brainstem center. We examine neuronal morphology and neuronal number in four control (average age = 15 years) and 9 autistic brains (average age = 15 years). This detailed investigation supports our previous descriptions of the MSO, and also reveals significant dysmorphology in five other SOC nuclei. Moreover, we provide evidence of a consistent and significant decrease in the number of SOC neurons in the autistic brain. Our studies implicate an extensive malformation of the auditory brainstem in the hearing and language difficulties in individuals with ASD. The results from this investigation suggest that neonatal testing of auditory function may aid in the identification of individuals with ASD earlier than presently possible.
Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with difficulties in the social, communicative, and behavioral domains. Most cases of ASD arise from an unknown etiologic ...process, but there are numerous risk factors, including comorbidities and maternal exposures. Although it is not part of the diagnostic criteria, hearing difficulties ranging from deafness to hyperacusis are present in the majority of persons with ASD. High-functioning children with ASD have been found to have significantly slower and asymmetric auditory brainstem reflexes. Additionally, histopathological studies of postmortem brainstems in decedents who had ASD have consistently revealed significantly fewer neurons in auditory nuclei compared with those in people who did not have ASD. The authors review the literature implicating auditory dysfunction in ASD along with results from human study participants and postmortem human brain tissue. Together, these results implicate significant structural and functional abnormalities in the auditory brainstem in ASD and support the utility of auditory testing to screen for ASD.
Abstract The critical period is a postnatal window characterized by a high level of experience-dependent neuronal plasticity in the central nervous system and sensory deprivation during this period ...significantly impacts neurological function. Perineuronal nets (PNNs) are specialized aggregates of the extracellular matrix which ensheath neuronal cell bodies, primary dendrites and axon hillocks and function in neuronal protection and stabilize synapses. PNNs are generally not present at birth, but reach adult-like patterns by the end of the third or fourth postnatal week. Their appearance is believed to mark the close of the critical period and sensory deprivation during this epoch disrupts development of PNNs. Here we investigate the postnatal development of two PNN markers ( Wisteria floribunda agglutinin WFA and Cat-315) and the effect of neonatal conductive hearing loss (CHL) on their development. Our data indicates that these PNN markers are not present in the superior olivary complex (SOC) at birth, but develop over the first four postnatal weeks in different temporal patterns and also that neonatal CHL results in a significant decrease in the number of SOC neurons associated with Cat-315 reactive PNNs.
•In utero exposure to VPA results in an increased risk of ASD in humans.•VPA exposure resulted in fewer neurons in the NLL and CNIC.•VPA exposure resulted in fewer CB+ neurons in the DNLL and smaller ...CB+ axons.•VPA exposure resulted in decreased dopaminergic innervation to the CNIC.
Prenatal exposure to the antiepileptic valproic acid (VPA) is associated with an increased risk of autism spectrum disorder (ASD) in humans and is used as an animal model of ASD. The majority of individuals with ASD exhibit adverse reactions to sensory stimuli and auditory dysfunction. Previous studies of animals exposed to VPA reveal abnormal neuronal responses to sound and mapping of sound frequency in the cerebral cortex and hyperactivation, hypoplasia and abnormal neuronal morphology in the cochlear nuclei (CN) and superior olivary complex (SOC). Herein, we examine the neuronal populations in the lateral lemniscus and inferior colliculus in animals exposed in utero to VPA. We used a combination of morphometric techniques, histochemistry and immunofluorescence to examine the nuclei of the lateral lemniscus (NLL) and the central nucleus of the inferior colliculus (CNIC). We found that the VPA exposure resulted in larger neurons in the CNIC and the dorsal nucleus of the lateral lemniscus (DNLL). However, we found that there were significantly fewer neurons throughout all nuclei examined in the auditory brainstem of VPA-exposed animals. Additionally, we found significantly fewer calbindin-immunopositive neurons in the DNLL. VPA exposure had no impact on the proportions of perineuronal nets in the NLL or CNIC. Finally, consistent with our observations in the CN and SOC, VPA exposure resulted in fewer dopaminergic terminals in the CNIC. Together, these results indicate that in utero VPA exposure significantly impacts structure and function of nearly the entire central auditory pathway.
Departments of 1 Otolaryngology-Head and
Neck Surgery, 2 Neurobiology and Anatomy,
3 Physiology and Pharmacology, and
4 The Sensory Neuroscience Research Center, West
Virginia University ...School of Medicine, Morgantown, West Virginia 26506
Kulesza Jr., Randy J.,
George A. Spirou, and
Albert S. Berrebi.
Physiological Response Properties of Neurons in the Superior
Paraolivary Nucleus of the Rat. J. Neurophysiol. 89: 2299-2312, 2003. The superior paraolivary
nucleus (SPON) is a prominent nucleus of the superior olivary complex.
In rats, this nucleus is composed of a morphologically homogeneous
population of GABAergic neurons that receive excitatory input from the
contralateral cochlear nucleus and inhibitory input from the
ipsilateral medial nucleus of the trapezoid body. SPON neurons provide
a dense projection to the ipsilateral inferior colliculus and are
thereby capable of exerting profound modulatory influence on collicular
neurons. Despite recent interest in the structural and connectional
features of SPON, little is presently known concerning the
physiological response properties of this cell group or its functional
role in auditory processing. We utilized extracellular, in vivo
recording methods to study responses of SPON neurons to broad band
noise, pure tone, and amplitude-modulated pure tone stimuli.
Localization of recording sites within the SPON provides evidence for a
medial (high frequency) to lateral (low frequency) tonotopic
representation of frequencies within the nucleus. Best frequencies of
SPON neurons spanned the audible range of the rat and receptive fields
were narrow with V-shaped regions near threshold. Nearly all SPON
neurons responded at the offset of broad band noise and pure tone
stimuli. The vast majority of SPON neurons displayed very low rates of spontaneous activity and only responded to stimuli presented to the
contralateral ear, although a small population showed binaural facilitation. Most SPON neurons also generated spike activity that was
synchronized to sinusoidally amplitude-modulated tones. Taken together,
these data suggest that SPON neurons may serve to encode temporal
features of complex sounds, such as those contained in species-specific vocalizations.
1 Departments of OtolaryngologyHead and Neck Surgery, Neurobiology and Anatomy and the Sensory Neuroscience Research Center, West Virginia University School of Medicine, Morgantown, West Virginia; ...and 2 Auditory Research Center, Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania
Submitted 13 June 2006;
accepted in final form 15 November 2006
The superior paraolivary nucleus (SPON) is a prominent periolivary cell group of the superior olivary complex. SPON neurons use -aminobutyric acid (GABA) as their neurotransmitter and are contacted by large numbers of glycinergic and GABAergic punctate profiles, representing a dense inhibitory innervation from the medial nucleus of the trapezoid body (MNTB) and from collaterals of SPON axons, respectively. SPON neurons have low rates of spontaneous activity, respond preferentially to the offset of pure tones, and phase-lock to amplitude-modulated tones. To determine the roles of glycine and GABA in shaping SPON responses, we recorded from single units in the SPON of anesthetized rats before, during, and after application of the glycine receptor antagonist strychnine, the GABA A receptor antagonist bicuculline, or both drugs applied simultaneously. Strychnine caused a major increase in spike counts during the stimulus presentation, followed by the disappearance of offset spikes. In half of the recorded units, bicuculline caused moderately increased firing during the stimulus. However, in 86% of units bicuculline also caused a large increase in the magnitude of the offset response. Application of the drug cocktail caused increased spontaneous activity, dramatically increased spike counts during the stimulus presentation, and eliminated the offset response in most units. We conclude that glycinergic inhibition from the MNTB suppresses SPON spiking during sound stimulation and is essential in generating offset responses. GABAergic inhibition, presumably from intrinsic SPON collaterals, plays a subtler role, contributing in some cells to suppression of firing during the stimulus and in most cells to restrict firing after stimulus offset.
Address for reprint requests and other correspondence: A. Berrebi, Sensory Neuroscience Research Center, PO Box 9303, Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV 26506-9303 (E-mail: aberrebi{at}hsc.wvu.edu )
•Neonatal excitotoxic injury impacts hair cells and spiral ganglion neurons.•MSG exposure results in fewer neurons in the CN and SOC.•MSG exposure results in nonuniform loss of GBC and MNTB ...neurons.•ABR waves were smaller and had long latency after MSG exposure.•Neonatal injury results in nonuniform loss of neurons and abnormal circuitry.
Excitotoxic injury during the neonatal period has been shown to result in neurodegenerative changes in several different brain regions. Exposure to monosodium glutamate (MSG) during the first two postnatal weeks results in glutamate neurotoxicity in the cochlea and has been shown to result in damage to cochlear hair cells and fewer neurons in the spiral ganglion. Further, we have shown that such exposure results in fewer neurons in the cochlear nucleus and superior olivary complex and abnormal expression of the calcium binding proteins calbindin and calretinin. Based on these findings, we hypothesized that neonatal MSG exposure would result in loss of neurons at more rostral levels in the auditory brainstem, and this exposure would result in abnormal brainstem auditory evoked potentials. We identified a significantly lower density of neurons in the spiral ganglion, heterogenous loss of neurons in the globular bushy cell-trapezoid body circuit, and fewer neurons in the nuclei of the lateral lemniscus and central nucleus of the inferior colliculus. The most severe loss of neurons was found in the inferior colliculus. Click-evoked auditory brainstem responses revealed significantly higher thresholds and longer latency responses, but these did not deteriorate with age. These results, together with our previous findings, indicate that neonatal exposure to MSG results in fewer neurons throughout the entire auditory brainstem and results in abnormal auditory brainstem responses.
•VPA exposure resulted in lower body weights, smaller brains and delayed eye and ear opening.•VPA exposure resulted in fewer CN and SOC neurons, reduced CB and CR expression and diminished TH+ ...innervation.•After VPA exposure, tz axons had smaller diameters but calyx terminals were enlarged relative to MNTB somata.
Auditory dysfunction is a common occurrence in individuals with autism spectrum disorder (ASD). While most cases of ASD are of unknown etiology, in utero exposure to the antiepileptic valproic acid (VPA) significantly increases risk. We have previously identified significant dysmorphology and hypoplasia in the auditory brainstem of humans with ASD and rodents exposed to VPA in utero. Further, we have identified abnormal c-Fos immunolabeling patterns after exposure to pure tone stimuli in VPA-exposed animals. Herein, we describe the impact of repeated exposure to VPA on key components of the auditory hindbrain, the ventral cochlear nucleus (VCN) and superior olivary complex (SOC). Specifically, we examined neuronal number, neuronal morphology, immunolabeling for the calcium binding proteins calbindin (CB) and calretinin (CR), dopaminergic innervation and the structure of calyx terminals in the medial nucleus of the trapezoid body (MNTB). VPA-exposed animals had significantly fewer neurons in both the VCN and SOC. VPA had a differential impact on the size of neurons in the VCN and SOC. VPA-exposed animals have reduced CB and CR immunolabeling and a lower density of dopaminergic terminals. Finally, we saw no difference in the surface area or volume of calyx terminals in the MNTB, although there was a relative increase in the surface area and volume of calyces in VPA-exposed animals. These results indicate hypotrophy of the auditory brainstem, abnormal calcium regulation and reduced dopaminergic input. Together, such alterations suggest abnormal brainstem circuitry and significant auditory dysfunction in VPA-exposed animals.
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