CHAPTER FOUR
PHYSIOLOGICAL ROLE OF THYROID HORMONE ON MEMORY
4.1 THYROID HORMONE RECEPTOR FOUND IN THE BRAIN (HIPPOCAMPUS)
Most recent efforts to define the mechanism by which thyroid hormone facilitates brain development and brain function are based on the assumption that thyroid hormone action proceeds along a nuclear pathway generally similar to that operating in other tissues (Boyages et al., 1993). Specific nuclear receptors for T3 in adult rat brain were first identified by in vivo saturation analysis after the intravenous injection of 125-I labeled T3 ,together with increasing concentrations of unlabeled T3(liony et al., 1998). Subsequently, an in vitro techniques were developed to detect and quantitate receptors in the brains of fetal rat,sheep, and human. The recognition that these sites in the brain exhibited high affinity and specificity for biological active thyroid hormone analogs strongly suggested that these structures represent the site of initiation of thyroid hormone action. The common and vital relationship between the brain(hippocampus) and thyroid hormone, is the thyroid hormone receptor (Aloy et al., 2010), which is a nuclear receptor functioning as hormone-activation transcription factors (Yen et al., 2004). Mammalian thyroid hormone receptors are encoded by two genes, designated alpha and beta (Crantz et al., 1982). Further, the primary transcript for each gene can be alternately spliced, generating different alpha and beta isoforms. There are two TR-a receptor splice variants encoded by the THRA gene and two TR-b isoform splice variants encoded by the THRB gene. That is TR-a1, TR-a2, TR-b1, TR-b2 (Heuer et al., 2003).
Thyroid hormone primarily mediates their effects by binding to thyroid hormone receptor isoform predominantly TR-a1 and TR-b1, which are expressed in various tissues (Wahlstrom and Naar, 2009). Notably , the ability to respond to T4 and T3 differs for the two TR isoforms, with TRa1 generally more responsive to T4 than TRb1(Arnold et al., 2001).TRa1 is abundantly expressed in the brain and resonds to both T3 and T4 playing active role in brain physiology(Peng et al.,1997).TRa1 is widely distributed in the CNS from E14 to adulthood(Peng et al., 1999). TRa1 is present in the outer part of the cerebral cortex and the hippocampal CA1 (Gerges et al., 2004).During the late fetal stage the TRa1 become expressed in the piriform cortex, superior colliculus and pyramidal layer of the hippocampus and also at the granular layer of the dentate gyrus(Missiaen and Blanco, 2003). In adulthood, TRa1 is expressed at the cerebral cortex, cerebellum, hippocampus, stratium and olfactory bulb (Missiaen et al., 2003). Critical roles in CNS development are known to be mediated by TRa1 including TH-dependent oligodendrocytes differentiation. The commitment of this cells as oligodendrocytes is therefore believed to linkd to cell specific TRa1 expression while the availability of TH regulates timing differentiation (Richman and Meister, 1975). Aditionally, TRa1 is known to exhibit important role in later stages of neurodevelopment and its expression persist to adulthood. Although the effective concentration of T4 in the brain is difficult to determine, it is plausible that T4 levels are sufficient to induce activation of TRa1- regulated genes in the brain even in the absence of T3(Dringen et al., 2006).
Thyroid hormone regulate adults hippocampal neurogenesis, a process involved in key function, such as learning, memory and mood regulation. We addressed the role of thyroid hormone receptor TRa1 in adult hippocampal neurogenesis , using mice harboring a TRa1 null allele (TRa1 -/-) , overexpressing TRa1 6 fold (TRa2 -/-) and a mutant TRa1 (TRa1 +/m) with a 10 –fold lower affinity to the ligand. While hippocampal progenitor was unaltered, TRa1-/- mice exhibited a significant increased endoublecortin-positive immature neurons and increase survival of bromodeoxyuridine-positive progenitors as compared to wild type controls.in contracts, the TRa1+/m and the TRa2-/- mice, where the over expressed TRa1 acts as an aporeceptor, showed a significant decline in surviving bromodeoxyuridine-positive progenitrs. TRa1-/- and TRa2-/- mice showed opposing effects on the neurogenic markers like polysialylated neural cell adhesion molecule and stathmin. Decreased proginator survival in the TRa2-/- and TRa1+/m mice could be rescue by thyroid hormone treatment, as was the decline in neuronal differentiation seen in the TRa1+/m mice. These mice also exhibited a decrease in neuroD cell numbers in the dentate gyrus, suggesting an effect on early postmittic progenitors (Wallis, Dudazy and Van, 2010). Our results provide the first evidence of a role for unliganded TRa1 in modulating the deleterious effects of hypothyroidism on adult hippocampal neurogenesis.
In human TR mutation or delation gives rise to syndrome involving resistance to thyroid hormone which is recognized clinically by increase in serum level of both TSH and TH, thus physiological action of TH is eliminated totally.
4.2 THYROID HORMONE EFFECT ON BETA-AMYLOID PROTEIN
Amyloid are aggregates of protein that becomes folded into wrong shape allowing many copies of that protein to stick together, making healthy tissue to lose their normal physiological function thus playing a role in neurodegeneration (Hsiao et al 1996).
Thyroid hormone plays critical role on prevention of beta amyloid protein which is harmful to neurons by releasing free radicals (Holcomb et al). Beta amyloid protein is the hallmark of Alzheimer's disease (Gordon et al, 1993) which involves memory retardation. Thyroid hormone negatively regulate amyloid beta precursor protein (APP) gene (Morgan et al., 1992) in thyroid hormone receptor transfected neuroblastoma cell. A negative thyroid hormone response element (nTRE) that mediates this regulation (Dicky et al.2003) has been identified in the first exon of the beta amyloid precursor protein (APP). APP protein and APP secreatase cleavage in mouse brain is influenced by Thyroid status (Guzowski et el. 2001). Amyloid beta protein precursor gene product expression was increase in hypothyroid mouse brain and decreses in hyperthyroid mouse brain (Austin et al. 2003). Expatiating, the incidence of hypothyroidism increase with age and localized hypothyroidism of central nervous system has been reported in patients having Alzheimer disease. Reduced action of thyroid hormone on amyloid beta precursor protein gene results to Alzheimer disease due to increase in amyloid plaques (Mayford et al. 1995, 1996).
4.3 THYROID-SEROTONINERGIC (5-HT) SYSTEM
Thyroid hormone plays an important role in a physiological mechanism called memory engram, in which serotonin plays an important function (Gur et al., 1999). Serotonin which is a neurotransmitter helps in molecular basis of facilitation (zuskib et all.,2000). On deplorisation, action potential causes the release of serotonin thus facilitating synaptic transmission to a great extent leading to memory (Vaidya et al.,2001). Recent studies in animal and human has shown that thyroid hormone influences the activity of serotonin as well as its receptors. Thyroid hormone increases serotonergic neurotransmission (Tejani-Butt et al., 1993)through two main independent mechanism namely; (1) By loss of autoinhibitory serotonergic receptor type 1A sensitivity mediated by T3 leading to an increase in cortical and hippocampal serotonin release(Bauer and Whybrow, 2001) (2). By increasing cortical serotonergic receptor type 2 (5-HT2) sensitivity (Heal and Smith,1998), creating a potential independent way of increasing 5-HT transmission. In human, serotonin plasmatic levels are positively correlated to T3 concentrations, being increased in hyperthyroidism and decreased in hypothyroidism (Cleare et al, 1995). In animals with hypothyroidism, found decreased in sensitivity of serotonin receptors and compensatory increase in the density of autoinhibitory serotonin receptors, secondary to the reduction in the level of synaptic serotonin (Kirkegaard and faber, 1999).
Other source of the evidence for the interaction of serotonin with thyroid hormone alteration originates from the studies with enzymes that metabolizes the thyroid hormones (Kirkegaard and faber, 1999). As seen before, intrabrain T3 is mainly the result of local production through deiodination of T4 by type 2 deiodinase enzyme and D2 enzymatic activity is increased in the hypothyroidism and decreases in hyperthyroidism(wushy et al.,2000). D2 activity increase the production of T3 in the brain and hypophysis and consequently also the local production of serotonin. Supposed that D2 activity decreases, the local concentration of T3 and indirectly both cortical and hippocampal serotonin also decreases. General effects of hypothyroidism on serotonin include;
Decrease cortical and hippocampal serotonin concentration.
Decrease quality of peripheral serotonin.
Decrease 5-HT density in the brain.
Increase serotonin turnover in the brain stem
Diminished central and peripheral serotonergic activity
Decreases 5-HT receptor sensitivity
Upregulation of auto inhibitory 5-HT receptor
4.4 THYROID HORMONE ON MEMORY MODULATION
Both systemic and intracerebral glucose administration are known to modulate memory(Bilezikian and Leob, 1983) .There are at least two major hypotheses for the mechanism by which systemic glucose administration can enhance memory;(1) By increasing the glucose supply to the brain through the blood brain barrier glucose transporter 1(GLUT1) and by (2) By affecting vagal activity which alters neurotransmission within the brain (Puymirat et al., 1985). As seen in normal physical activity, in which too much work results to skeletal muscle fatique, so is in the brain. The hippocampal memory activity results in hippocampal glucose drainage thus reducing energy production, leading to memory impairment. At this junction, thyroid hormone can function in increasing hippocampal glucose thereby improving memory.
Brain glucose metabolism is regulated by TH at multiple levels (Asan et al. 2006).PET studies suggested that the link between thyroid activity and brain glucose metabolism. Brain hypometabolism is commonly observed in thyroid disorders (Kincaid et al 2001).Clinical data suggested that there is a significant and global decrease in brain glucose metabolism in severe hypothyroidism of short duration and that both neural activity and regional glucose metabolism are in reduced the brain (Prange et al 1995) of mild–moderate hypothyroid patients especially in the hippocampus, bilateral amygdala, left subgenual and cingulate gyrus (Mano et al 1981).
Preclinical studies have provided insight into several specific potential mechanisms for TH regulation of glucose metabolism which include the following;
Activation of sympathetic nervous system-Administration of T3 increases glucose production as long as sympathetic input to the liver is intact to ensure gluconeogenesis and glycogenolysis (Deng and Song, 2011).
Modulation of glucose transporter-Which include the GLUT1 and GLUT4, increasing glucose uptake from gastrointestinal system (Deng et al., 2011).
Interaction with glucocorticoid signaling –Both endogenous and exogenous glucocorticoid impairs glucose metabolism. In both peripherial tissue and hippocampus, elevated glucocorticoid level impairs GLUT4 functioning(Smith et al., 2002).Hepatic glucose increases, peripheral glucose use by the muscle, increase in proinsulin output and increase in insulin clearance(Obregon et al., 2004) all leading to increase in blood glucose level(glycemia), thus maintain brain glucose level which in turn modulating memory.
Administration of glucose or insulin causes markedly increased hippocampal glucose metabolism enhancing memory performance. However activity of a key consumer of glycolytic ATP called NA+K+ATPase, is decreased by 45% in the hippocampi (Hamburgh et al, .,1971 ;Nicholson and Altman, 1972b) of both hypo and hyperthyroid patient suggesting potential role of thyroid hormone on regulation of hippocampal glucose metabolism.
4.5 MEMORY MODULATION BY THYROID-GABANERGIC MECHANISM
Apart from memory modulation by brain glucose homeostasis mechanism due to gluconeogenic intrinsic function of thyroid hormones, Thyroid hormone on Gaba can modulate memory (Bernal et al 2002).
Gamma aminobutyric acid is the chief inhibitory compound found in a mature vertebrate central nervous system (Ford and Cramer, 1977; Patel et al., 1980a).Gaba is the most important neurotransmitter in the central nervous system.Human brain contain about 20-30% Gabanergic neuron in the brain (Cramer et al.2000).On stimulation, Gaba inhibit neuronal excitation by activating chloride ion inflow in the cell (Wiens and Trudeau, 2006).
The hippocampus is a unique structure containing Gaba receptor, I.e GABA-A and GABA-B receptor (Yoshimura et al 2005) and its isoforms. Alpha1-4, beta2 and gamma2 are well distributed at the strata radiatum of CA1 and CA3.beta1 is located at the CA2 region while the alpha4 and delta subunits is predominant at CA1 than CA3 (Ramire de Guglielmone and Gomez, 1966).
Experimental evidence has suggested that Gaba System is sensitive to thyroid hormone(Balaz et al ,1968),underscoring the significants of the experimental evidence that TH regulates brain function by modulating Gaba function in the brain.The possibility that thyroid hormone affects Gabanergic activity was recognized in 1960's.Invivo studies on rat brain has been discovered that T3 application accelerate the developmental increase in glutamic aminoacid decarboxylase which converts glutamic acid to Gaba (Trudeau et al 1997).High level of TH stimulate gaba activity while low level decrease it. Thyroid hormone can also stimulate Gaba receptor sensitivity. TH also affect the activity of other enzyme involve in the Gaba metabolism pathway (Garcia Argiz et al 1967) example Gaba transaminase and succinate semialdehyde dehydrogenase.
Mechanism-Under the influence of thyroid hormone at the synaptosomes, calcium ion acts on the membrane containing vesicles and release Gaba via exocytosis (Krawiec et al 1969). Gaba on reaching at the hippocampus causes the sticking of new information and regulates generation of new information (smisky et al 2008). Variation in local level of gaba in the vicinity of individual synapse are responsible for the difference in synaptic strength and this difference facilitate new memories (Sandrini et al 1991). Higher concentration of Gaba in synapse weakens synaptic strength (Mason et al 1990) due to its inhibitory action thus making synapse more liable to form new memories (Agrawal et al 1997). In the light of behavioural finding, it is tempting to speculate that decrease in Gabanergic inhibition could lead to potentiation of strength at which hippocampal-dependent fear memories are stored and reduce the capacity to forget negative information is no longer relevant(smisky et al 2008). This is clearly not a behavioural advantage because excessive and prolong hippocampal activation leads to structural damage inhibiting synaptic plasticity (Cremaschi et al 2000) and memory impairment. As sleep is essential for memory consolidation, so is Gabanergic system under the influence of thyroid hormone.
4.6 EFFECTS OF THYROID DYSFUNCTION ON HIPPOCAMPUS
A reduction in dentate gyrus granule cell (Madeira et al., 1991).
A decrease in pyramidal cell spine densities (Gould et al., 1990).
Decrease in number and size of dendritic spine of purkinje cells (Giardino et al., 1995; Calza et al., 1996).
A decrease in the branching of apical and basal dendrites granule and pyramidal cells (Legend et al., 1997).
Iodine deficiency causes an impaired maturation of hippocampal radial glial cells, which are involved in neuronal migration (Rami et al., 1989).
Perinatal hypothyroidism inhibits migration of dentate granule cells, decreases cell number and reduces the dendritic aborization (Malanka et al., 1993).
Retardation in migration of migrating cells from the proliferative zone to the granule cell layer of the dentate gyrus (Rami and Rabie, 1990).
Increases neuronal death and impaired dendritic aborization result in irreversible reduction in total granule cell number, volume of granule cell layer, cell densities and synapse number (Thompson and Potter, 2000).
A reduction or absence, of thyroid hormone during brain development yield maturation, morphological, and functional alterations in the hippocampus (Lee et al., 2003).
Transient neonatal hyperthyroidism produces an altered hippocampal morphology with larger mossy fiber terminal fields in the hippocampal CA3 region. These morphological changes are accompanied by an improvement of spatial memory (Koornstra et al., 1999; Reid and Wheeler, 2005).
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