Thyroid Hormone Action: Nongenomic Modulation of Neuronal Excitability in the Hippocampus

Abstract

Years of effort have failed to establish a generally-accepted mechanism of thyroid hormone (TH) action in the mature brain. Recently, both morphological and pharmacological evidence have supported a direct neuroactive role for the hormone and its triiodinated metabolites. However, no direct physiological validation has been available. We now describe electrophysiological studies in vivo in which we observed that local thyroxine (T4) administration promptly inhibited field excitatory postsynaptic potentials recorded in the dentate gyrus (DG) with stimulation of the medial perforant pathway, a result that was found to be especially pronounced in hypothyroid rats. In separate in vitro experiments, we observed more subtle but statistically significant responses of hippocampal slices to treatment with the hormone. The results demonstrate that baseline firing rates of CA1 pyramidal cells were modestly reduced by pulse-perfusion with T4. By contrast, administration of triiodothyronine (T3) was often noted to have modest enhancing effects on CA1 cell firing rates in hippocampal slices from euthyroid animals. Moreover, and more reliably, robust firing rate increases induced by norepinephrine were amplified when preceded by treatment with T3, whereas they were diminished by pretreatment with T4. These studies provide the first direct evidence for functional, nongenomic actions of TH leading to rapid changes in neuronal excitability in adult rat DG studied in vivo and highlight the opposing effects of T4 and T3 on norepinephrine-induced responses of CA1 cells studied in vitro.

Experimentally Induced Hyperthyroidism Disrupts Hippocampal Long-Term Potentiation in Adult Rats

“…In parallel with our findings, it was reported that the efficacy of LTP induction was significantly attenuated in T3-treated rats, indicating that neonatal hyperthyroidism disturbs LTP in the DG of the hippocampal formation [36]. Furthermore, local T4 microinjection in the DG in normothyroid and propylthiouracil-treated rats produced an immediate and long-lasting decrease in the PS amplitude recorded from the DG following stimulation of the medial perforant pathway [51]. Interestingly, depressed I/O relationships [42,44] and impaired LTP [42,44] were also pronounced in hypothyroid rats.…”

Frank Beach Award Winner: Steroids as neuromodulators of brain circuits and behavior

“…Our view of what defines the properties of a neuromodulator has recently undergone a major expansion to include molecules like oxide gases, endocanabinoids, hydrogen sulfides, thyroxine, and steroids (Balthazart and Ball, 2006; Caria et al, 2009; Saldanha et al, 2011; Snyder, 2009). For example, nitric oxide appears to act as a stabilizing neuromodulator in the control of multiple movements patterned by a gut CPG in a mollusc (Dyakonova and Dyakonova, 2010).…”

“…Owing to their somewhat peculiar chemistry, most of these nonclassical modulators are not packaged into vesicles for conventional release by neurons, and their release properties and interactions can be comparatively complex (e.g., Boychuk et al, 2013; Huang and Woolley, 2012). Thyroxine itself may share similarities with steroids in terms of ‘synaptocrine’ signaling in the brain, including nongenomic effects (Caria et al, 2009; Davis et al, 2007), a distribution of bouton-like beads along fibers coursing through cortex (Rozanov and Dratman, 1996), and a hypothesized role as neurotransmitters (Dratman and Gordon, 1996; Greenberg et al, 2006). Our understanding of the group of molecules that can modulate neural circuits is now expanding, which illuminates the flexibility afforded to neural circuits to respond to varying internal and external states and generate many flexible outputs.…”

Effects of acute microinjections of the thyroid hormone derivative 3-iodothyronamine to the preoptic region of adult male rats on sleep, thermoregulation and motor activity

“…Injection of T1AM to the locus coeruleus (LC) resulted in an increase in firing of a subset of neurons (Dhillo et al, 2009; Gompf et al, 2010). In contrast, hippocampal cells showed a rapid decrease in excitability upon local administration of T4 in anesthetized rats (Caria et al, 2009). Administration of norepinephrine and norepinephrine agonists to the preoptic region rapidly decreased EEG-defined sleep (Mohan Kumar et al, 1986; Ramesh and Kumar, 1998; Ramesh et al, 1995).…”