Expression of tuberin mRNA in tissues

cells of the cerebellum and motor Table 1. Degree of TSC2 gene expression in varineurons in the medulla at high levels, ous types of neuronsand (ii) that the intermediate levels ofBrain region
Neuron type
TSC2 gene
TSC2 signals are expressed in mostexpression
neurons of the cerebral cortex, septum,++
striatum, reticular formation in the Cerebral cortex Most neurons
SeptumMost neurons+
medulla and substantia nigra compacta.
+++In the brains from individuals Piriform cortex Most neurons
Striatum
Medium neurons++
affected with TSC, cortical tubers,
Large interneurons+++
periventricular nodules and giant cell Hippocampus
Pyramidal cells+++
Dentate granule cells+++
astrocytoma are the characteristicHelus neurons+++
lesions (Gomez, 1988). These+
hamartomas in the central nervous Substantia nigra Neurons of the pars compacta
Cerebellum
Purkinje cells+++
system are considered to be due to errors
Granule cells+
in differentiation and migration of Medulla
Neurons of reticular formation+
Neurons of the facial nucleus+++
germinal cells (Nishimura et al., 1985),
which result from loss of heterozygosity Degree of expression: +++, high; ++, moderate; +, slight.
for the TSC2 gene observed in theabnormal tissues. Because of theheterozygosity of TSC2 DNA markers on spikes (Wong et al, 1979; Llinas and Sugimori,chromosome 16p13.3 in most affected cells, a 1980; Ross and Werman, 1987; Tank et al.,lesser amount of TSC2 products must be 1988; Regehr et al 1989; Jaffe et al., 1992;
observed in normal tissues of the brain from Yuste et al., 1994). In contrast to the abundantTSC patients. However, neurons in the normal expression of the TSC2 gene in these large- ortissues from TSC patients do not exhibit any medium-sized neurons, cells in the cerebellar
other degenerative features, even with the granule layer which were characterized by their
reduced amount of TSC gene products. To- tiny cell size and poor dendritic structures
gether with this lack of degenerative features of (Palay and Chan-Palay, 1974) expressed aneurons in the brain from TSC patients, from lesser amount of TSC2 signals, despite having
the present finding on the high levels of TSC2 the highest cell density in the layer. Also, small
gene expression in the specific types of neurons non-neural cells like oligodendrocytes or astroin the normal brain, the possibility emerges that cytes which exist abundantly in the striatal
the function of TSC2 gene products in mature regions rich in dendrites and fiber tracts appearneurons may be quite other than proliferation, ed not to be stained by TSC2 mRNA signals, asseen in the radiatum, oriens and molecular layer
differentiation or a tumor suppressor function.
The most abundant expression of the TSC2 of the hippocampus (Fig. 2).
Current studies on the molecular and cellgene was exhibited specifically in large- ormedium-sized neurons of the hippocampal ular basis for memory and learning have accupyramidal layer, dentate granular layer, piri- mulated evidence that the hippocampal pyramiform cortex, striatum, cerebellar purkinje cell dal neurons, dentate granule cells, corticallayer and medullary motor nucleus, which all pyramidal neurons and cerebellar purkinje cells
had the common feature of well-developed showed a long-term potentiation (LTP) (Blissdendritic trees (McGeer et al., 1978). Especial- and Lomo, 1973; Artola and Singer, 1987; Brownly, as novel imaging and electrophysiological et al., 1988; Bashir et al., 1991; Madison et al.,techniques have revealed, these cerebellar 1991; Bliss and Collingridge, 1993) or long-term
Purkinje neurons, cortical pyramidal and hippo- depression (LTD) (Ito et al., 1982; Kano andcampal pyramidal neurons have active den- Kato, 1987; Ito, 1989) thought of as activitydrites of which entire trees are covered with dependent long-term changes in synaptic efficalcium channels and demonstrate calcium cacy. On the other hand, the morphological61

M. Saji et al.

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sclerosis (Tsc2) gene locus in spontaneous uterine leiomyosarcomas and pituitary adenomas inbasis for memory and learning was consideredto lie in modifications of synaptic connectivities, especially in the activity-dependentchanges of the dendritic spines as a result of
intracellular molecular alterations in responseto repeated stimulation (Guthrie et al., 1991;
Muller and Connor, 1991; Lisman and Harris,1993; Shepherd, 1994). It has been reported
that the TSC2 gene product shares a region ofhomology with the GTPase-activating protein
for rap1 which is predicted to interact with rap1
(Wienecke et al., 1995). This relation of theTSC2 gene product with rap1, which functionsin the regulation of cytoskeletal interaction in
mammalian platelets and in the budding ofyeast cells (McCabe et al., 1992; White et al.,1992), strongly supports the notion that theTSC2 gene product may function in the formation of the dendritic spines, thus conferring
synaptic plasticity to neurons. Since neurons
showing the highest TSC2 expression were of
the cell types which were deeply involved inlong-term memories and were rich in synaptic
plasticity, it is likely that TSC2 gene products
play a role in building and maintaining thehigher functions of neuron networks for memory and learning.
Therefore, the possible function of the TSC2gene product in the formation of dendritic spines
and the use-dependent modification of synaptic
connectivities may be relevant to mental retardation observed in TSC patients.

Acknowledgments: This work was supported in partby a Special Grant for Neurocutaneous Disease from
the Ministry of Health and Welfare of Japan.
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(Received February 5, Accepted March 3, 1998)

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