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Abnormal morphology and subcortical projections to the medial geniculate in an animal model of autism

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Abstract

Auditory dysfunction, including hypersensitivity and tinnitus, is a common symptom of autism spectrum disorder (ASD). Prenatal exposure to the antiseizure medication valproic acid (VPA) significantly increases the risk of ASD in humans and similar exposure is utilized as an animal model of ASD in rodents. Animals exposed to VPA in utero have abnormal activity in their auditory cortex in response to sounds, fewer neurons, abnormal neuronal morphology, reduced expression of calcium-binding proteins, and reduced ascending projections to the central nucleus of the inferior colliculus. Unfortunately, these previous studies of central auditory circuits neglect the medial geniculate (MG), which serves as an important auditory relay from the midbrain to the auditory cortex. Here, we examine the structure and connectivity of the medial geniculate (MG) in rats prenatally exposed to VPA. Our results indicate that VPA exposure results in significantly smaller and fewer neurons in the ventral and medial nuclei of the MG. Furthermore, injections of the retrograde tract tracer fluorogold (FG) in the MG result in significantly fewer FG+ neurons in the inferior colliculus, superior olivary complex, and ventral cochlear nucleus. Together, we interpret these findings to indicate that VPA exposure results in hypoplasia throughout the auditory circuits and that VPA has a differential impact on some long-range axonal projections from brainstem centers to the thalamus. Together, our findings support the widespread impact of VPA on neurons and sensory circuits in the developing brain.

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Abbreviations

ASD:

Autism spectrum disorder

AVCN:

Anterior ventral cochlear nucleus

Cb:

Cerebellum

CL:

Contralateral

CN:

Cochlear nucleus

CNIC:

Central nucleus of the inferior colliculus

D:

Dorsal

DNLL:

Dorsal nucleus of the lateral lemniscus

DMW :

Dorsal medial wedge

E:

Embryonic

FG:

Fluorogold

FG+ :

Fluorogold positive

IC:

Inferior colliculus

IL:

Ipsilateral

L:

Lateral

ll:

Lateral lemniscus

LSO:

Lateral superior olive

M:

Medial

MG:

Medial geniculate

mMG:

Medial nucleus of the medial geniculate

MNTB:

Medial nucleus of the trapezoid body

MSO:

Medial superior olive

NLL:

Nuclei of the lateral lemniscus

NTR:

Neurotrace red

P:

Postnatal

PB:

Phosphate buffer

SD:

Standard deviation

SOC:

Superior olivary complex

SPON:

Superior paraolivary nucleus

STN:

Spinal trigeminal nucleus

stt:

Spinal trigeminal tract

tz:

Trapezoid body

V:

Vestibular nerve

VCN:

Ventral cochlear nucleus

vMG:

Ventral nucleus of the medial geniculate

VPA:

Valproic acid

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Authors and Affiliations

  1. Department of Anatomy, Lake Erie College of Osteopathic Medicine, 1858 West Grandview Blvd, Erie, PA, 16504, USA

    Yusra Mansour, Syed Naved Ahmed & Randy Kulesza

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  1. Yusra Mansour
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  2. Syed Naved Ahmed
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  3. Randy Kulesza
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Contributions

Randy Kulesza designed the study. Stereotaxic injections, perfusions, and tissue processing were done by Randy Kulesza and Yusra Mansour. Neuron counts and analysis of neuron morphology were done by Yusra Mansour and Syed Ahmed. The 3D model was made by Yusra Mansour. All authors have contributed to data analysis. The first draft of the manuscript was written by Randy Kulesza, and all authors have contributed to revisions and editing of the manuscript. Randy Kulesza and Yusra Mansour constructed all figures. All authors read and approved the final manuscript.

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Correspondence to Randy Kulesza.

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Mansour, Y., Ahmed, S.N. & Kulesza, R. Abnormal morphology and subcortical projections to the medial geniculate in an animal model of autism. Exp Brain Res 239, 381–400 (2021). https://doi.org/10.1007/s00221-020-05982-w

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