Thyroid hormones are essential to preserve non-proliferative cells of adult neurogenesis of the dentate gyrus.

Thyroid hormones (THs) regulate adult hippocampal neurogenesis, a process that involves both cell populations that dynamically switch between pools of proliferative and quiescent cells, and cells that definitely leave the cell cycle to maturate into granular neurons. This investigation was carried out to determine the role of THs on the mitotic activity of specific proliferative cell populations and the preservation of non-proliferative cells participating in the neurogenic process of the dentate gyrus (DG) of the hippocampus. Hypothyroidism was induced in male adult Wistar rats with methimazole for 28days. We quantified the total number of proliferative cells (BrdU+), proliferative type 1 (BrdU+/GFAP+), and 2b and 3 (BrdU+/DCX+) cells. Early non-proliferative cells (BrdU-/DCX+ cells lacking dendritic process), postmitotic neuroblasts (Tuj 1+ cells lacking dendritic process), and immature granular neurons (IGN; DCX+ or Tuj 1+ and the presence of dendritic processes into granular or molecular layer) were also included. The evidence showed that the proliferation of Type 1, 2b and 3 cells is not modified by hypothyroidism. In contrast, hypothyroidism reduced the number of early non-proliferative cells and also leads to a decrement in the number of IGN. Our results show that proliferative cells of the DG are not sensitive to thyroid perturbations. However, THs are essential to preserve cell populations that leave the cell cycle in the DG of the hippocampus.

Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats.

Severe thyroid hormone (TH) deficiency during critical phases of brain development results in irreversible neurological and cognitive impairments. The mechanisms accounting for this are likely multifactorial, and are not fully understood. Here we pursue the possibility that one important element is that TH affects basal and activity-dependent neurotrophin expression in brain regions important for neural processing. Graded exposure to propylthiouracil (PTU) during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. In contrast to small PTU-induced reductions in basal expression of several genes, developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes (Bdnft, Bdnfiv, Arc, and Klf9) in adulthood and was accompanied by deficits in hippocampal-based learning. These data demonstrate that mild TH insufficiency during development not only reduces expression of important neurotrophins that persists into adulthood but also severely restricts the activity-dependent induction of these genes. Considering the importance of these neurotrophins for sculpting the structural and functional synaptic architecture in the developing and the mature brain, it is likely that TH-mediated deficits in these plasticity mechanisms contribute to the cognitive deficiencies that accompany developmental TH compromise.

Adult onset-hypothyroidism: alterations in hippocampal field potentials in the dentate gyrus are largely associated with anaesthesia-induced hypothermia.

Thyroid hormone (TH) is essential for a number of physiological processes and is particularly critical during nervous system development. The hippocampus is strongly implicated in cognition and is sensitive to developmental hypothyroidism. The impact of TH insufficiency in the foetus and neonate on hippocampal synaptic function has been fairly well characterised. 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. In the present study, we report hypothyroidism induced by the synthesis inhibitor propylthiouracil (10 p.p.m., 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 anaesthesia, 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 anaesthesia necessary for surgical procedures posed a thermoregulatory challenge that was differentially met in control and hypothyroid animals. Minor increases in field potential EPSP slope, decreases in PS amplitudes and increased latencies are consistent with previous reports of hypothermia in naive control rats. 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 the synaptic impairments observed in adult offspring following developmental TH insufficiency, and emphasise 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.

Hypothyroidism reduces glutamate-synaptic release by ouabain depolarization in rat CA3-hippocampal region.

Thyroid hormones modulate the physiology of the hippocampus in humans, where glutamate plays an important role as neurotransmitter. The aim of this work was to study the effect of hypothyroidism on hippocampal glutamate extracellular levels, release, uptake, and synthesis. The effects of PDC (a glutamate transporter inhibitor) and ouabain (a Na(+) /K(+) -ATPase inhibitor) infusion on microdialysate glutamate and aspartate levels of CA3 hippocampal region were evaluated. Animals were assigned to one of the following groups: hypothyroid group (Hyp), receiving methimazole (anantithyroid drug); replacement group (Hyp + T(4) ), receiving antithyroid treatment plus thyroxine; and euthyroid control group (Eut). Dialysate fractions were collected every 15 min to determine basal glutamate levels for 1 hr. Then, PDC (10 mM) or ouabain (100 µM) was infused for 30 min. Results showed lower glutamate and aspartate basal levels in Hyp than in Eut groups. PDC infusion increased amino acids levels in all groups, whereas ouabain infusion increased glutamate and aspartate levels only in the Eut group. The infusion of tetrodotoxin (TTX; a voltage-gated sodium channel inhibitor) prevented the glutamate increase in euthyroid rats. The Hyp + T(4) group showed glutamate levels similar to those found in the Eut group. Additionally, glutaminase activity in hippocampus was lower in the Hyp group than in the Eut or Hyp + T(4) group. Results suggest that high-affinity glutamate transporters are not altered by hypothyroidism; however, decreased hypotyroidism reduced vesicular glutamate release in the CA3-hippocampal region as a consequence of diminished glutamate synthesis.