Perinatal methimazole exposure impairs the distribution and function of layer 5 neurons in the mouse auditory cortex

Abstract

Abstract Methimazole (MMI) is an antithyroid drug often prescribed for hyperthyroid conditions. While perinatal MMI exposure is used to model hypothyroidism in rodents, resulting in auditory cortex malformation, mice are reportedly less effective in lowering serum thyroxine levels. This raises the question on MMI-induced hypothyroidism being the underlying cause of cortical malformation. Here we examined if and how perinatal MMI exposure in mice influenced the serum thyroxine level and the distribution and function of deep layer projection neurons in the auditory cortex. MMI exposure resulted in little changes in the thyroxine level and in auditory brainstem responses. However, MMI exposure misdistributed Ctip2-immunopositive, corticocollicular neurons (CCNs) toward the white matter in layer 5, independent of thyroid hormone-sensitive neurogranin expression. Morphologically, the MMI exposure increased immature dendritic spines in apical dendrites of pyramidal neurons without affecting the number of mature spines. Functionally, excitatory synaptic activities were elevated in retrogradely-identified CCNs and callosal projection neurons (CPNs), while the excitability of these neurons was differentially elevated in both cell types. MMI increased spike induction probability and decreased burst-like spike amplitude ratio in CCNs, while it decreased spike threshold and increased burst-like spike amplitude ratio in CPNs. MMI exposure consequently decreased neural circuit activity in the deep layers. These data indicate that perinatal MMI exposure could impair cortical development, dendritic spine maturation, and neuronal properties of layer 5 neurons without lowering the serum thyroxine level, implicating that maternal MMI exposure thyroid-independently endangers auditory cognition in the offspring.

Keywords

• Auditory cortex
• Cortical development
• Dendritic spines
• Hypothyroidism
• Neuronal excitability
• Thyroid