Journal of Neuroendocrinology

From Molecular to Translational Neurobiology

Journal of Neuroendocrinology 20, 784–794
ª 2008 The Author. Journal Compilation ª 2008 Blackwell Publishing Ltd
REVIEW ARTICLE

Neurodevelopmental and Neurophysiological Actions of Thyroid Hormone

G. R. Williams
Molecular Endocrinology Group, Division of Medicine & MRC Clinical Sciences Centre, Imperial College, London, UK.

Journal of For over 100 years, thyroid hormones have been known to be essential for neonatal neurodevel-
opment but whether they are required by the foetal brain remains a matter of controversy. For
Neuroendocrinology decades, the prevailing view was that thyroid hormones are not necessary until after birth
because circulating levels in the foetus are very low and the placenta forms an efficient barrier
to their transfer from the mother. Clinical observations of good neurological outcome following
early treatment of congenital hypothyroidism were used to support the view that thyroid hor-
mones are not required early in neurodevelopment. Nevertheless, the issue remained contentious
because of findings that the severity of foetal neurological deficit due to maternal iodine defi-
ciency correlated with the degree of maternal thyroxine (T4) deficiency. Furthermore, neurologi-
cal damage in these cases could be prevented by correction of maternal T4 deficiency before
mid-gestation. This observation led to the opposing view, supported by epidemiological studies
of neurological cretinism, that maternal thyroid hormones are important and necessary for early
foetal neurodevelopment. It is now clear that thyroid hormones are essential for both foetal and
post-natal neurodevelopment and for the regulation of neuropsychological function in children
and adults. In recent years, this controversial subject has progressed very rapidly following
remarkable progress in understanding of the molecular mechanisms of thyroid hormone action.
Correspondence to: This article reviews the contributions of molecular biology and genetics to our new understand-
Graham R. Williams, Molecular
ing of the physiological effects of thyroid hormones on neurodevelopment and in the adult
Endocrinology Group, MRC Clinical
Sciences Centre, Hammersmith brain.
Hospital, Du Cane Road,
Key words: thyroid hormones, thyroid hormone receptor, brain, development, behaviour.
London W12 0NN, UK
(e-mail: graham.williams@imperial.
ac.uk). doi: 10.1111/j.1365-2826.2008.01733.x

eral signs of hypothyroidism (7). Although endemic cretinism can

Thyroid hormones and neurodevelopment
Thyroid hormones have no influence on very early developmental
events, such as neural induction and establishment of polarity,
but regulate later processes, including neurogenesis, myelination,
dendrite proliferation and synapse formation (1–3). Numerous
thyroid hormone responsive genes have been identified (1) and
the timing of the onset of thyroid hormone action in the devel-
oping brain is crucial (3–6). For example, endemic neurological
cretinism is due to maternal iodine deficiency and the resulting
maternal hypothyroxinaemia, which is defined as thyroxine (T4)
concentrations that are low for the stage of pregnancy. Low
maternal T4 levels cause neurological hypothyroidism in the
foetus, which results in profound mental retardation, cerebral
spastic diplegia, deaf-mutism and squint in the absence of gen-
be prevented by public health measures, such as iodine supple-
mentation, that prevent or correct first trimester maternal hypo-
thyroxinaemia, iodine deficiency remains the commonest
endocrine disorder worldwide and the most frequent cause of
preventable mental retardation (4). By contrast, neurological fea-
tures in neonatal hypothyroidism are less severe, dependent on
the severity of hypothyroidism and largely preventable by imme-
diate thyroid hormone replacement, although deficits in memory
and IQ may persist (3). Untreated neonates exhibit growth retar-
dation and general features of hypothyroidism with mental retar-
dation, tremor, spasticity and speech and language deficits (3, 7).
Differences between endemic cretinism and congenital hypothy-
roidism illustrate that the timing of thyroid hormone action is
fundamental for neurodevelopment.
 Thyroid hormone action in the brain 785

ptogenesis, together with the initiation of glial cell differentiation

Timing of thyroid hormone action in the brain
Three stages of thyroid hormone dependent neurological develop-
ment can be recognised (Fig. 1). The first occurs before the
onset of foetal thyroid hormone synthesis, which occurs at
16–20 weeks postconception in humans or by embryonic day
E17.5–18 in the rat. During this period, thyroid hormone expo-
sure comes only from maternally synthesised hormone (4–6, 8)
and influences neuronal proliferation and migration of neurones
in the cerebral cortex, hippocampus and medial ganglionic emi-
nence (9–12). The second stage occurs during the remainder of
pregnancy after the onset of foetal thyroid function when the
developing brain derives its supply of thyroid hormones from
both the foetus and the mother (4–6, 8). During this period,
thyroid hormone dependent processes include neurogenesis, neu-
rone migration, axonal outgrowth, dendritic branching and syna-
and migration and the onset of myelination (1, 7, 8). The third
stage occurs in the neonatal and post-natal period when thyroid
hormone supplies to the brain are entirely derived from the child
and critical for continuing maturation. During this period, migra-
tion of granule cells in the hippocampal dentate gyrus and cere-
bellum, pyramidal cells in the cortex and Purkinje cells in the
cerebellum are sensitive to thyroid hormones and thyroid hor-
mone-dependent gliogenesis and myelination continues (1, 7, 8).
Maternal and foetal thyroid physiology
Before the onset of foetal thyroid function, low levels of T4 and
3,5,3¢-L-triiodothyronine (T3) of maternal origin are present in
embryonic fluids and tissues, including the brain (13–16). Foetal
T4 and T3 levels correlate with maternal T4 rather than T3 (16),

1st Trimester 2nd Trimester 3rd Trimester Post-natal

14/40 28/40 Term 6/12

Neurone proliferation

Onset of neurone migration

Cortex
Hippocampus
Cochlea
Cerebellum

Myelination
Glial cell proliferation
Synapse formation
Axon & dendrite migration/branching
T4 levels
(pmol/l)
20
10
0
Maternal Maternal + Fetal Neonate
Expression
of TRs Apo-TRs Occupied TRs

Thyroid gland Thyroid hormone

formation production

D3 Fetal TSH D2

1st Trimester 2nd Trimester 3rd Trimester Post-natal

14/40 28/40 Term 6/12

Fig. 1. Relationship between thyroid hormone action and development of the brain. In the first trimester of pregnancy early neuronal proliferation and migra-
tion is dependent on maternal thyroxine (T4). In foetal tissues, inactivating type 3 deiodinase (D3) enzyme expression falls and development of the thyroid
gland commences. By the end of the first trimester, development of the hypothalamic-pituitary axis has occurred and a surge in thyroid-stimulating hormone
(TSH) secretion results in the onset of foetal thyroid hormone production, expression of the activating type 2 iodothyronine deiodinase enzyme (D2) and
increasing occupation of thyroid hormone receptors (TRs) by 3,5,3¢-L-triiodothyronine (T3). Continuing development of the brain in the second and third trimes-
ters relies increasingly on T4 produced by both the foetus and mother. Continued post-natal development is entirely dependent on neonatal thyroid hormone
production. Apo-TR, unliganded unoccupied thyroid hormone receptor.

ª 2008 The Author. Journal Compilation ª 2008 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 20, 784–794
786 G. R. Williams
and T3 derived from maternal or foetal serum barely contributes
to brain T3 levels (13). Importantly, during the first trimester,
there is a surge in maternal T4 accompanied by inhibition of
thyroid-stimulating hormone (TSH) that results from high concen-
trations of placental chorionic gonadotrophin at approximately
10–12 weeks of gestation (17). This has been interpreted to
reflect an increase in maternal thyroid hormone production
imposed by the conceptus, which thus ensures an adequate sup-
ply of maternal T4 to the foetus during the critical period of
early thyroid hormone-dependent neurodevelopment (4, 5). This
need for increased thyroid hormone production and heightened
vulnerability to maternal thyroid status also arises because of
the increased volume of distribution of thyroid hormones in
plasma, their increased metabolism and turnover in pregnancy
and the effects of oestrogens on thyroid hormone binding pro-
teins. Accordingly, maternal hypothyroxinaemia rather than
T3-deficiency prior to the onset of foetal thyroid function results
in abnormal neuronal migration and neocortical cyto-architecture
(12, 18). The necessity for increased thyroid hormone require-
ments in pregnancy has also been highlighted by clinical studies
demonstrating the need for increased thyroid hormone replace-
ment in pregnant women with hypothyroidism (19, 20).
Utero–placental transfer of thyroid hormones
Surprisingly, levels of total T4 in foetal fluids are 100-fold lower
than levels in maternal serum, and T3 concentrations are lower
still (15, 16). This paradox is resolved by the finding that free
T4 levels in the foetus are comparable to maternal concentrations
(15). The free T4 fraction in the foetus is higher than in the
mother because of differences in T4 binding proteins. Thus, the
availability of free T4 to foetal tissues is dependent on maternal
T4 levels and decreases significantly in situations of maternal hyp-
othyroxinaemia. By analogy, if the total thyroid hormone levels in
the mother and foetus were similar, foetal tissues would be
exposed to elevated levels of free T4 and free T3 (4, 5) that are
also detrimental to the critical temporal sequence of thyroid hor-
mone responses during foetal development (21). These consider-
ations underlie the requirement for an efficient but incomplete
utero–placental barrier to maternal thyroid hormone transfer that
limits supplies and ensures that ‘euthyroid’ free hormone concen-
trations are maintained in foetal fluids and tissues. Following the
onset of foetal thyroid hormone production, levels of total and
free T3 remain very low in the foetus compared to the mother,
whereas total and free T4 concentrations reach adult levels by the
beginning of the third trimester (22). Despite the increasing con-
centrations of T4 in the foetus as gestation progresses, the foetal
thyroid reserve remains low and the gland does not mature fully
until birth (23). Thus, maternal thyroid hormones continue to con-
tribute to foetal T4 levels until birth, as demonstrated in neonates
who cannot synthesise their own thyroid hormones because of
complete organification defects (24). Likewise, hypothyroxinaemia
in premature babies results from a complete absence of maternal
T4 and may account in part for their increased risk of cerebral
palsy and neurological deficit (3, 4, 25).
ª 2008 The Author. Journal Compilation ª 2008 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 20, 784–794
Delivery of thyroid hormones to target tissues
Thyroid hormones are lipophilic and poorly soluble in water. They bind
reversibly to plasma transport proteins of varying affinity, which
include thyroxine-binding globulin (TBG), transthyretin (previously
called thyroxine-binding prealbumin), albumin and various lipopro-
teins. The free-fractions of circulating thyroid hormones are depen-
dent on the concentrations and saturations of binding proteins and
in normal serum free T4 represents 0.02% of the total T4 concentra-
tion, whereas free T3 is 0.3% of total T3 because of its lower affinity
for TBG. As a result, total circulating concentrations of T4 are 50–
60-fold higher than total T3, whereas free T4 levels are only approxi-
mately four-fold higher than free T3. Circulating T4 is derived solely
from synthesis and secretion by the thyroid gland, whereas 80% of
circulating T3 is produced in peripheral tissues by enzymatic removal
of an outer ring 5¢-iodine atom from T4. Both T4 and T3 are trans-
ported into target tissues with equal efficiency and do not compete
for uptake. Until recently, the mechanism of cellular entry of free thy-
roid hormones was not clear but was presumed to occur by passive
diffusion because of their lipophilic nature (26). In fact, the hormones
enter target cells and cross the placenta via an energy-dependent,
ATP-requiring, stereospecific and saturable transport mechanism that
is mediated by the monocarboxylate transporter-8 (MCT8) (27) and
other transporter proteins such as OATP1c1, a member of the Na+-
independent organic anion transporter protein (OATP) family (28, 29).
Thyroid hormone action
Thyroid hormone receptors (TRs) bind T3 with high affinity and
function as ligand-inducible transcription factors that regulate
expression of T3-responsive target genes. TRa and TRb are members
of the steroid ⁄ thyroid hormone receptor superfamily and were orig-
inally cloned in 1986 (30, 31). The TRa gene (THRA, NR1A1) encodes
three C-terminal variants in mammals: TRa1 binds T3 and DNA and
is a functional receptor, whereas TRa2 and TRa3 do not bind
T3 and are weak dominant negative antagonists in vitro, although
their roles in vivo are unclear (32). A promoter that generates two
truncated variants, TRDa1 and TRDa2, has also been identified in
intron 7 of murine Thra. TRDa1 and TRDa2 are potent repressors
of TR function in vitro but their physiological significance
is also unknown (33). The TRb gene (THRB, NR1A2) encodes two
N-terminal variants in all vertebrates TRb1 and TRb2, both of which
are functional receptors. Additional variants, TRb3 and TRDb3, are
expressed in rats but their physiological role is not known (34, 35).
Unlike most nuclear receptors, unliganded apo-TRs compete with
liganded TRs for DNA response elements and act as potent repres-
sors that exert important physiological roles during the develop-
ment of specific tissues including the brain (36–39). Apo-TRs
interact with co-repressor proteins, which recruit histone deacety-
lases and maintain a nonpermissive chromatin structure to inhibit
gene transcription. By contrast, liganded TRs bind to coactivators in
a T3-dependent manner. Coactivators possess intrinsic histone ace-
tyl transferase activity, which facilitates formation of permissive
nucleosomes and activation of gene expression. Thus, the opposing
effects of unoccupied and occupied TRs result in a greatly increased
 Thyroid hormone action in the brain 787

amplitude of transcriptional response to T3 (32, 37). TRa1 and TRb1 ties acts as a critical homeostatic regulator of T3 availability to the
are expressed in most tissues but their relative abundance varies cell nucleus even at extremes of thyroid function. In the brain, D2
and this may represent a mechanism for control of T3 action in a activity is markedly up-regulated in the presence of low thyroid
temporo-spatial specific manner (40). Although circulating levels of hormone levels (54), whereas D3 activity is strongly decreased (55).
free T4 are four-fold higher than free T3, the TR has at least a This adaptation is thought to protect the susceptible brain from
15-fold greater affinity for T3 (41), indicating that T4 is a prohor- normal fluctuations in circulating thyroid hormone levels as well as
mone that must be converted to T3 prior to the onset of thyroid to some extent protecting from the detrimental effects of hypothy-
hormone action (42). roidism or hyperthyroidism, particularly during development (13, 29,
56). Thus, local regulation of thyroid status in specific regions of
the brain is achieved by the coordinated regional expression of the
Thyroid hormone metabolism
D2 and D3 enzymes (57) and T3 homeostasis results from compen-
The iodothyronine deiodinases are selenoenzymes that activate or satory reciprocal changes in activities of the D2 and D3 enzymes
inactivate thyroid hormones. The type 2 deiodinase (D2) catalyses (44, 58, 59).
removal of an outer ring iodine atom from the prohormone T4 with
an apparent Michaelis constant (Km) of 10)9M to generate the
Control of T3 availability and action in the brain
active product T3. By contrast, the D3 isozyme inactivates T3, or
prevents T4 being activated, by catalysing removal of an inner ring The main cellular site of T3 action in the brain is the neurone, but
iodine with a Km of 10)9M to generate 3,3¢-diiodothyronine (T2) or T3 must gain access to neurones by a circuitous route that is sub-
3,3¢,5¢-triiodothyronine (reverse T3, rT3) respectively. The D1 enzyme ject to local regulation (29, 60, 61) (Fig. 2). The highly specific iodo-
is inefficient with a Km of 10)6–10)7M and catalyses removal of thyronine transporters OATP1c1 and MCT8 are both expressed in
inner or outer ring iodine atoms in equimolar proportions to gener- the central nervous system (CNS) and, in the last 5 years, our
ate T3, rT3 or T2 depending on the substrate. Most circulating T3 is
derived from T4 by the actions of D1 in liver and kidney, although
D2 in skeletal muscle also contributes (42–44). Nevertheless, the T4
OATP1c1
primary action of D2 is to determine the intra-cellular concentra-
tion of T3 and level of saturation of the nuclear TR. Its lower Km Blood Endothelium
T4 T3
enables efficient local generation of T3 at times of T4 deprivation
and D2 is thought to protect vital structures from periods of hypo- OATP1c1 ?
thyroidism. Accordingly, T4 treatment of cells coexpressing the T4
T4 Astrocyte
MCT8 transporter and D2 activating enzyme results in increased T3 T3 CP D2 T3
MCT8 ?
production and hormone responsiveness (27), demonstrating a
functional link between thyroid hormone uptake and metabolism in T3
the regulation of T3-action. By contrast, the inactivating D3 iso- TR
zyme prevents thyroid hormone access to specific tissues at critical Neurone
T4 T4 T3 T3 T3
times and reduces TR-saturation (42, 44). MCT8 D2
MCT8 D3
Astrocyte T2

Tissue thyroid status CSF

D3 is expressed in foetal tissues and the placenta where it initially
prevents maternal thyroid hormone access to the developing foetus
(45). At this time, unoccupied TRs are critical factors that generally
maintain cell proliferation and prevent differentiation (37, 46). The
sharp rise in T3 availability at birth in mammals is analogous to the
T3-dependent metamorphosis climax in amphibians (47) and a simi-
lar period at hatching in birds (48), and depends on tightly regu-
lated temporo-spatial expression of D2 and D3 (49). Increased
pituitary D2 expression correlates with maturation of the hypotha-
lamic-pituitary-thyroid (HPT) axis whereas its expression in
T3-target tissues, concomitant with reduced expression of D3,
results in conversion of unoccupied TRs into occupied TRs and the
initiation of cell differentiation (46, 47, 50–53) (Fig. 1). Thus, the TR
acts as a deiodinase-dependent developmental switch that regu-
lates maturation of T3-dependent tissues. Expression of D2 is
increased in hypothyroidism whereas D3 expression is increased in
thyrotoxicosis, ensuring that the balance between D2 and D3 activi-
T3
Tanycyte
Fig. 2. Delivery of thyroid hormones to neurones. Circulating thyroid hor-
mones enter the cerebrospinal fluid via the choroid plexus, which expresses
both monocarboxylate transporter-8 (MCT8) and Na+-independent organic
anion transporter protein 1c1 (OATP1c1) thyroid hormone-specific trans-
porter proteins. The prohormone, T4 is transported across the blood–brain
barrier via OATP1c1 in endothelial cells or MCT8 in tanycytes lining the third
ventricle. Thyroxine (T4) enters glial cells including astrocytes via an
unknown mechanism and is activated to 3,5,3¢-L-triiodothyronine (T3) via
the activating type 2 iodothyronine deiodinase (D2) enzyme. T3 is exported
from glial cells by an unknown transporter to facilitate MCT8-dependent
entry into neurones. T3 may also enter neurones directly from blood or
cerebrospinal fluid (CSF) by a poorly defined route. T3 acts via thyroid hor-
mone receptors (TRs) expressed in neurones or is metabolised by the inacti-
vating type 3 deiodinase (D3) enzyme to inactive 3,3¢-diiodothyronine (T2).
CP, choroid plexus;?, unknown transporter protein.

ª 2008 The Author. Journal Compilation ª 2008 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 20, 784–794
788 G. R. Williams
understanding of thyroid hormone uptake into the brain has pro-
gressed remarkably. Most likely, control of local T3 levels in brain
tissue takes place in functional units of astrocytes and neurones
(62). T4 (and T3) must first cross the blood–brain barrier, and the
T4-specific transporter OATP1c1 is ideally placed to achieve this as
it is expressed at high levels in capillary endothelium throughout
the CNS (63, 64). Some T3 transport across the blood–brain barrier
may also be mediated by MCT8 (65). Thyroid hormones also enter
via the choroid plexus–cerobrospinal fluid (CSF) barrier. OATP-1 and
MCT-8 are expressed in choroid plexus and likely to mediate trans-
port of T4 (65), whilst MCT8 and D2 are coexpressed in tanycytes
lining the third ventricle and facilitate access of thyroid hormones
to hypothalamic nuclei and thyrotrophin-releasing hormone (TRH)
neurones (56, 65–67). Having entered the CNS, T4 is taken up by
astrocytes via an unidentified transporter, where it is converted to
T3 via local activity of D2 (66, 67). T3 generated in astrocytes is
then transported out of the cell via an unknown transporter before
active uptake into neurones is mediated via MCT8 (65, 67). T3 then
exerts its major actions directly in neurones by regulating expres-
sion of T3-target genes (2, 68, 69). T3 is finally metabolised and
degraded by D3 in neurones (59, 67). This model, which proposes
that T3 supply to neurones is dependent on D2 activity in astro-
cytes, has been challenged recently by observations in mutant mice
lacking D2. Compared with wild-type littermates D2-knockout mice
have a very mild neurological phenotype, indicating that T3 supply
to the brain can also be obtained directly from serum and CSF to
compensate for the lack of D2 activity in astrocytes (70).
Thyroid hormone transport in the brain
In situ hybridisation studies have shown MCT8 mRNA is expressed
at high levels in choroid plexus, olfactory bulb, cerebral cortex, hip-
pocampus and amygdala, at moderate levels in striatum and cere-
bellum and at low levels in some neuroendocrine nuclei.
Colocalisation studies revealed that MCT8 is predominantly
expressed in neurones. Together with a spatiotemporal pattern of
MCT8 expression during the perinatal period, these data indicate
that MCT8 plays an important role in CNS development by trans-
porting thyroid hormones into neurones (65). MCT8 is also
expressed in pituitary folliculo-stellate cells (71), the same cells that
express TSH receptor and may be involved in ultra-short feedback
control of TSH secretion (72, 73). In support of this view, MCT8
protein is expressed in human hypothalamic paraventricular, supra-
optic and infundibular nuclei and in the lining of ependymal cells
of the third ventricle, which are all locations involved in negative
feedback of TRH (67).
MCT8 mutations in humans
A key physiological role for thyroid hormone transport was con-
firmed in patients with mutations in SLC16A2 (previously MCT8)
located on chromosome Xq13.2 (74, 75). Affected boys have an
unusual thyroid status characterised by elevated T3 concentrations
with reduced T4 and reverse T3 levels and inappropriately normal
ª 2008 The Author. Journal Compilation ª 2008 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 20, 784–794
or modestly elevated TSH. The characteristic abnormalities are
accompanied by a severe, X-linked, psychomotor retardation syn-
drome that presents in early childhood and is thought to result
from defective neuronal T3 entry causing abnormal T3 action and
metabolism (62). There is global developmental delay including poor
communication skills, no speech development, poor head control,
mental retardation and varying degrees of truncal hypotonia, athe-
toid movements and motor deficiency, which may include spastic
quadriplegia in severe cases. The neurological phenotype of X-linked
psychomotor retardation in patients with SLC16A2 mutations clo-
sely resembles Allan–Herndon–Dudley syndrome (OMIM 300523),
originally described in 1944 (62, 76–79).
MCT8-deficient mice
To investigate the role of MCT8, two laboratories generated MCT8-
deficient mice (80, 81). Similar to patients with SLC16A2 mutations,
MCT8-deficient mice had increased circulating T3, reduced T4 and
reverse T3 with modestly elevated or normal levels of TSH. Hepatic
D1 activity was increased and an important contributor to increased
circulating T3 (80, 81). MCT8-deficient mice had reduced uptake of
radiolabelled T3 into brain tissue, whereas T4 entry was not
impaired (81). Nevertheless, tissue concentrations of T4 and T3 in
brain were reduced. Despite increased D2 activity and reduced D3
clearance (80, 81), the presence of tissue hypothyroidism demon-
strates that increased local T3 production and decreased T3 catabo-
lism only compensates partially for MCT8 deficiency (81). Despite
these metabolic changes, no neurological abnormalities were
observed in MCT8-deficient mice, suggesting there are only minor
consequences to impaired neuronal T3 entry in development of the
murine CNS. In particular, the cerebellum, which is especially sensi-
tive to thyroid hormones during development, was unaffected with
normal proliferation, migration and dendrite formation in Pukinje
and granule cells (81). Nevertheless, markedly elevated hypotha-
lamic TRH expression that did not respond to injected T3 was iden-
tified in MCT8 mutants, confirming the presence of impaired
neuronal T3 entry. By contrast, TRH was inhibited by T4 injection,
indicating that TRH neurones still respond to T4, which acts
presumably following D2-mediated local conversion of T4 to T3.
Similarly, pituitary TSH responsiveness to T3 was impaired in MCT8-
deficient mice (80, 81). These data suggest the presence of
additional neuronal thyroid hormone transporters in developing
mouse brain (29, 60).
Thyroid hormone metabolism in the brain
Type 2 deiodinase
The activating D2 enzyme is expressed in glial cells, third ventricle
tanycytes, astrocytes and some sensory neurones including nuclei
within the trigeminal, auditory and visual pathways (56, 58, 66).
Understanding of key neurodevelopmental roles for D2 has come
from a series of elegant studies in mice. In the cochlea, D2 is
expressed in periosteal connective tissue surrounding the internal

sensory tissues, with enzyme activity peaking before the onset of
hearing. TR expression, however, is localised to the cochlea sensory
epithelium, suggesting that periosteal D2 provides a spatiotempo-
rally regulated supply of T3 to the sensory epithelium that is neces-
sary for correct timing of the development and maturation of the
cochlea (50). This hypothesis was supported by the finding that
D2-deficient mice exhibit delayed cochlea development and defec-
tive auditory function despite circulating levels of thyroid hormones
that normally are permissive for development of hearing. Thus,
D2-dependent local generation of T3 to the cochlea is essential for
auditory function (52). In this case, the activating D2-enzyme func-
tions as a local amplifier of T3 action to regulate sensory develop-
ment. By contrast, the inactivating D3 enzyme can influence
spatiotemporal development of sensory pathways by inhibiting
T3 action locally. For example, D3 regulates localised asymmetrical
growth of the dorsal retina during development of the eye in Xeno-
pus by reducing local T3 concentrations to inhibit T3-dependent
proliferation of lateral projecting ganglion cells (82).
D2-deficient mice also have elevated circulating T4 and TSH lev-
els but normal T3 concentrations and display an impaired negative
feedback TSH response to T4 but not T3, demonstrating that D2 is
required for local T3 generation in the pituitary and essential for
normal control of the HPT axis (83). Additionally, neonatal D2
knockout mice have 25–50% reduced tissue T3 concentrations
throughout the brain, although levels of expression of T3-target
genes (RC3, TrkB, Hairless, Srg1) were either unaffected or much
less affected when compared to alterations in hypothyroid brain
(70). Consequently, and although D2 expression is increased mark-
edly in neonatal rat brain during the critical period of neuronal
development (49), D2-deficient mice exhibit a very mild general
neurological phenotype compared with abnormalities seen in hypo-
thyroid mice. Thus, although neuronal T3 is thought to be derived
primarily from D2-dependent metabolism of T4 in glial cells, these
findings suggest compensatory mechanisms can ameliorate the
neurological consequences of D2 deficiency and that other sources
of T3 are available to the brain during its development (70) (Fig. 2).
Expression of MCT8 in cerebral cortex and cerebellum was similar in
wild-type, D2 knockout and hypothyroid mice, indicating that com-
pensation for D2 deficiency is unlikely to involve increased MCT8-
mediated T3 uptake (70).
Type 3 deiodinase
The inactivating D3 enzyme is highly expressed in the developing
rat brain (49) and is also present in neurones throughout the adult
rat brain especially in pyramidal cells of the hippocampus, granule
cells in the dentate and in cerebral cortex (59). In early studies, hetero-
geneous levels of D3 enzyme activity were detected throughout the
brain (84). Studies in D3-deficient mice have also revealed a critical
role for this enzyme in maturation and activity of the HPT axis at
the levels of the hypothalamus, pituitary and thyroid gland. As a
result, neonatal D3-deficient mice are thyrotoxic because of delayed
T3 clearance, whereas, after post-natal day 15, mutants exhibit cen-
tral hypothyroidism with impaired pituitary and thyroid responses
ª 2008 The Author. Journal Compilation ª 2008 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 20, 784–794
Thyroid hormone action in the brain 789
to TRH and TSH, respectively (85, 86). Accordingly, neonatal
D3-deficient mice, which have elevated circulating T3 but low T4
levels, show evidence of tissue thyrotoxicosis in the brain that is
accompanied by increased D2 activity (presumably due to low
circulating T4 levels). This increase in D2 activity in the face of
elevated circulating T3 concentrations results in increased tissue T3
levels and increased expression of T3-target genes (85), confirming
the key role for D3 in regulation of tissue thyroid status during
brain development and its intimate reciprocal relationship with the
activating enzyme D2.
Thyroid hormone receptors in the brain
TR expression
In the brain, TRs are expressed prior to the onset of foetal thyroid
hormone production (87). TRa1 is the major isoform expressed during
foetal life (68, 87) but, prior to birth, there is increased expression of
TRb1 (87, 88), which is distributed widely as development proceeds
(68, 69, 89). Nevertheless, TRa has been estimated to account for
70–80% of total TR expression in the brain (90). TRa1 and TRb1 also
exhibit differential spatiotemporal expression in neurones throughout
the post-natal and adult brain (68), suggesting discrete roles for the
two isoforms during development and in the mature CNS. For exam-
ple, in cerebellum, TRa1 is expressed in granular cells whereas both
TRa1 and TRb1 are present in Purkinje cells. Accordingly, T3 acts via
TRa1 to regulate granular cell migration and via both TRa1 and TRb1
to control Purkinje cell differentiation (91). Similarly, differences in
levels of TRa1 and TRb1 expression in GABAergic interneurones in
cerebral cortex and hippocampus correlate with behavioural pheno-
types characterised in TR mutant mice (92). Furthermore TRa1, but
not TRb, has been shown to regulate the onset of oligodendrocyte
precursor cell differentiation and control the timing of oligodendro-
cyte maturation and migration in the optic nerve (93, 94). The actions
of TRa1 and TRb1 in the brain, however, are not necessarily discrete;
recent studies have revealed cooperative interactions between the
two isoforms during astrocyte maturation (95). Expression of the
TRb2 isoform, by contrast, is localised and restricted to the hypothal-
amus (69, 96–98), anterior pituitary (99, 100), developing cochlea
(101) and neural retina (102).
Regulation of the HPT axis by TRs
In the hypothalamus and pituitary, TRb controls the HPT axis. Mice
lacking all TRb isoforms or harbouring a dominant negative knockin
mutation of Thrb display the biochemical features of resistance to
thyroid hormone (RTH) seen in patients with mutations in THRB
(103–108). TRb knockout mice or mice expressing dominant-nega-
tive TRb proteins display defective HPT axis regulation in both
hypothalamus and pituitary resulting in elevated T3 and T4 concen-
trations and inappropriately normal or elevated TSH (109, 110).
Gene transfer experiments also demonstrate an important role for
TRb in the regulation of TRH (111, 112). More specifically, TRb2-
deficient mice exhibit a similar degree of central RTH to mice with
790 G. R. Williams
complete deletion of all TRb isoforms, with defects also demon-
strated at the level of both pituitary and hypothalamus (96, 104).
Together, these data indicate a major role for TRb2 in regulation
and determination of the set-point of the HPT axis in vivo.
TRs and sensory development
In the auditory system, although the organ of Corti within the
cochlea expresses both TR isoforms, TRb has the major functional
role. TRb knockout but not TRa1-deficient mice display abnormal
cochlear development and defective auditory function (113, 114),
although additional deletion of TRa1 in compound mutants wors-
ens the cochlear abnormalities to reveal a cooperative role for TRa1
(113, 115). Both TRb1 and TRb2 are expressed in similar patterns in
the cochlea but mice with selective deletion of TRb2 display normal
auditory function (104, 116), indicating a primary role for TRb1 or
the ability of TRb1 to compensate for lack of TRb2 in development
of hearing. TRb-deficient mice also display increased susceptibility
to audiogenic seizures (117). The THRB gene is also important for
hearing in humans as severe deafness was described in a family
with recessive RTH caused by a deletion of THRB, whereas milder
sensori-neural deafness is a well-described feature in patients with
autosomal dominant RTH due to dominant negative mutations in
THRB (108). In the retina, TRb2 is expressed in developing photore-
ceptors and deletion results in a selective loss of M-cones but pres-
ervation of normal total cone number. All cones in TRb2 knockout
mice are S-opsin expressing, indicating that TRb2 is essential for
commitment of a sub-population of developing cones to the
M-opsin expressing phenotype (116, 118).
TRs and behaviour
Behavioural analysis of TR mutant mice has provided new insight
into the regulation of cognition, memory and emotion by thyroid
hormones. Transgenic mice expressing a dominant-negative TRb dis-
play stereotypic behavioural features reminiscent of attention-defi-
cit-hyperactivity disorder (119), a condition that also occurs in
human RTH (108). Female TR knockout mice display abnormal mat-
ing; TRa1-deficient mice have suppression of female receptiveness,
whereas this behaviour is enhanced in TRb mutants (120). In
behavioural tests, including the open field test, Morris water maze,
Y maze and contextual fear conditioning, TRb knockout mice
perform normally (107). By contrast, TRa1 deficient mice display
freezing responses to open-field testing and a poor response to con-
textual fear conditioning. These findings suggest TRa1 deficient mice
display high emotionality and negative memory persistence (92).
Studies in mice with a point mutation in TRa1 (121) revealed evi-
dence of anxiety with reduced exploratory behaviour and memory
deficiencies, which are defects that could be improved following
T3 administration at very specific time periods (38). Further analysis
demonstrated abnormalities of motor skills and locomotion in adults
that were dependent on adequate supplies of thyroid hormone dur-
ing early and late foetal development as well as continuing supplies
in the post-natal period and adulthood (39). These recent data reveal
ª 2008 The Author. Journal Compilation ª 2008 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 20, 784–794
a novel role for TRa1 in the development and maintenance of
behavioural responses and motor coordination and may provide new
insight into the molecular pathogenesis of neuronal damage result-
ing from congenital hypothyroidism or endemic cretinism.
The future
New details regarding the molecular basis for thyroid hormone
transport, metabolism and action has resulted in a transformation
of our understanding of neurological development and behaviour.
There are many new opportunities for the future, however, as
understanding remains in its infancy. For example, most of the
T3-target genes identified in the brain are regulated during early
development (1) and a remaining challenge will be to identify
T3-regulated genes in the post-natal period and those that are
associated with behavioural responses in adults. Understanding of
the role of MCT8 in the brain is advanced; the precise role of
OATP1c1 is less clear but abundant evidence suggests the presence
of additional transporters mediating thyroid hormone influx and
efflux, especially in glial cells. The neurobiology of thyroid hormone
transporters will be an expanding field in the near future. New
insights into TR-isoform specific actions in different regions of the
brain have developed alongside an understanding of TR-isoform
specific actions in other tissues. These breakthroughs have led to
the development of TR-isoform selective analogues (122). Thus, the
TRb-selective agonists GC-1 and KB2115 have beneficial effects on
cholesterol and lipid metabolism but lack the detrimental effects of
T3 to the heart and skeleton (123, 124). As a result, safety and effi-
cacy studies have begun with KB2115 in humans (124). TRa1
antagonists have the potential for the selective treatment of car-
diac arrhythmias or the prevention of bone loss (40, 122, 125).
Despite this progress, behavioural and motor defects identified in
TRa1 mutant mice and behavioural abnormalities in TRb mutants
emphasise the need for further characterisation of the role of TR
isoforms in the adult brain. The effects of TR analogues on behav-
iour will be an important avenue for the future. Along these lines,
it has always been intriguing that patients with RTH have muta-
tions restricted to the THRB gene encoding TRb (108). No individu-
als with mutations in THRA have been defined. Close analysis of
the unexpected neurological and behavioural phenotypes of TRa1
mutant mice may lead to the identification of individuals with
THRA mutations and provide a place for TRs in the arena of molec-
ular psychiatry.
This review has focused on the traditional genomic mechanisms
of thyroid hormone action mediated via nuclear receptors. Space
has not allowed discussion of nongenomic and rapid membrane
responses to thyroid hormones (126, 127). These have hardly been
studied in the brain, but it is likely they will have important contri-
butions for the future. There is excitement ahead for thyroid
research in neuroendocrinology!
Received: 13 March 2008,
revised 27 March 2008,
accepted 28 March 2008

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