EPA Science Inventory

Adult Onset-Hypothyroidism: Alterations in Hippocampal Field Potentials in the Denate Gyrus are Largely Associated with Anesthesia-Induced Hypothermia

Citation:

Sanchez-Huerta, K., J. Pacheco-Rosado, AND M. Gilbert. Adult Onset-Hypothyroidism: Alterations in Hippocampal Field Potentials in the Denate Gyrus are Largely Associated with Anesthesia-Induced Hypothermia. Journal of Neuroendocrinology. John Wiley & Sons Inc, Malden, MA, 27(1):8-19, (2015).

Description:

Thyroid hormone (TH) is essential for a number of physiological processes and is particularly critical during nervous system development. The hippocampus is a structure strongly implicated in cognition and is sensitive to developmental hypothyroidism. The impact of TH insufficiency in the fetus and neonate on hippocampal synaptic function has been fairly well characterized. Although adult onset hypothyroidism has also been associated with impairments in cognitive function, studies of hippocampal synaptic function with late onset hypothyroidism have yielded inconsistent results. Here we report hypothyroidism induced by the synthesis inhibitor propylthiouracil (PTU, 10 ppm, 0.001%, minimum of 4 weeks), resulted in marginal alterations in excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude in the dentate gyrus measured in vivo. No effects were seen in tests of short-term plasticity, and a minor enhancement of long-term potentiation of the EPSP slope was observed. The most robust synaptic alteration evident in hypothyroid animals was an increase in synaptic response latency which was paralleled by a failure to maintain normal body temperature under anesthesia, despite warming on a heating pad. Latency shifts could be reversed in hypothyroid animals by increasing the external heat source, and conversely, synaptic delays could be induced in control animals by removing the heat source with a consequent drop in body and brain temperature. Thermoregulation is TH­ dependent, and anesthesia necessary for surgical procedures posed a thermoregulatory challenge that was differentially met in control and hypothyroid animals. Minor increases infield potential EPSP slope, decreases in PS amplitudes, and increased latencies are consistent with previous reports of hypothermia. We conclude that failures in thyroid-dependent temperature regulation rather than direct action of TH in synaptic physiology are responsible for the observed effects. These findings stand in contrast to synaptic impairments observed in adult offspring following developmental TH insufficiency, and underscore the need to control for the potential unintended consequences of hypothermia in the interpretation of hypothyroid-induced changes in physiological systems, most notably, synaptic transmission.

Purpose/Objective:

The EPA must evaluate the risk of exposure of the developing organism to chemicals with the potential to disrupt thyroid hormone (TH), and for which the degree of TH perturbation is likely to be fairly mild. The primary concern of altered TH status is the impact insufficient TH may have on the developing brain, especially in areas critical for cognition. We have characterized the effects of developmental hypothyroidism on synaptic transmission and plasticity in the hippocampus, a primary region in brain responsible for learning and memory, when hormonal status was altered in utero and the early postnatal period. It has also become clear in recent years that TH also alters functioning of neuronal circuitry in the adult brain. In the following paper we describe a series of endpoints, similar to those previously characterized in a developmental exposure model, in response to a 4-week exposure to the TH synthesis inhibitor, propylthiouracil (PTU) in adult rats. What we observed were a number of alterations in synaptic function and plasticity that were clearly induced by TH insufficiency in this model, but were quite distinct in nature from those observed in euthyroid adult offspring of hypothyroid dams. That is, all the physiological functional metrics evaluated were similar in the adult and developmental exposure scenarios and assessments were made in the adult rat regardless of when the exposure occurred. In contrast to impaired excitatory synaptic transmission, reduced inhibitory synaptic transmission, and impaired synaptic plasticity (synaptic model of memory in the hippocampus) typical of developmental exposure scenarios, adult onset hypothyroidism did not alter excitatory or inhibitory synaptic function and produced modest enhancements in synaptic plasticity. This is not to say that synaptic function was not impaired in the adult model. We observed, a very robust and consistent delay in synaptic transmission in hippocampal field potentials recorded in adult hypothyroid rats, an effect we have never observed in the developmental model. With more careful analysis we were able to discern that this delay in synaptic latencies was not a primary effect of hypothyroidism, but rather secondary to the effects of hypothermia induced by the anesthesia necessary for the experimental protocols. Despite continuous warming on a heating pad (standard procedure) over the prolonged time course dictated by our first set of experiments, body temperatures in PTU animals fell well below those at which control animals had stabilized. The attribution of the observed pattern of field potential amplitudes and latency shifts in PTU-treated animals to hypothermia rather than hypothyroidism was verified in the second experiment in which we could reverse the latency shift upon excessive warming in PTU animals, and evoke the same delayed latency profile in control animals with cooling. This double dissociation provides strong evidence of the contribution of temperature regulation to the synaptic impairments observed in hypothyroid animals under anesthesia, rather than a direct action of thyroid hormone insufficiency on brain function. Our findings further suggest that alterations in temperature regulation may not be evident at these more moderate degrees ofhypothyroidism during baseline measures, but emerge upon thermal challenge as induced here by anesthesia. These findings stand in contrast to synaptic impairments observed in adult offspring following developmental TH insufficiency, and reinforce the developing organism as the vulnerable population with regards to environmental thyroid disruptors. Furthermore, these findings underscore the need to control for the potential unintended consequences ofhypothermia in the interpretation ofhypothyroid-induced changes in physiological systems that include, but may not be limited to, synaptic brain function

URLs/Downloads:

https://doi.org/10.1111/jne.12229   Exit

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Completion Date: 01/01/2015
Record Last Revised: 11/22/2017
Record Created: 05/11/2015
Record Released: 05/11/2015
OMB Category: Other
Record ID: 307941

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY

TOXICOLOGY ASSESSMENT DIVISION

NEUROTOXICOLOGY BRANCH