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The Cerebellum 2002; 1: pp 201206

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Cell death in weaver mouse cerebellum


Amy B Harkins and Aaron P Fox
Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, Illinois, USA

Mice with the weaver mutation exhibit an uneven weave to their gait, ataxia, mild locomotor hyperactivity and, occasionally, tonic-clonic seizures. A single amino acid mutation in a G-protein coupled, inwardly rectifying K+ channel,
GIRK2, gives rise to the symptoms seen in the weaver mice. Two areas of the brain are primarily affected. Cerebellar
granule cell neurons die soon after birth and dopaminergic neurons are severely depleted in the substantia nigra. In
this article we review recent studies of wild-type and mutant GIRK channels found in native cells or introduced into
expression systems. We also review two models that explain some of the details leading to the neuronal cell death
observed in weaver mice.

Keywords:
GIRK K channel resting Ca2 cell death

Weaver phenotype
Throughout the last four decades, mutant mice have
been utilized as models to study neurological disorders,
neuronal degeneration and pathology. Spontaneous
mutations have given rise to distinctive phenotypes with
descriptive names such as staggerer, tottering, lurcher, and
shiverer. Many of these phenotypes are the result of a
pleiotropic mutation in which a single gene has multiple
and complicated effects on various cell types during
developmental and adult stages of the animal. One such
mutation is the weaver mutation, an inherited autosomal
recessive disease.12 The weaver mouse was initially
described as having an uneven weave to its gait and
ataxia due to cerebellar abnormalities.3 Later studies
reported that the weaver mouse also exhibits mild locomotor hyperactivity,4 male sterility5 and, occasionally,
tonic-clonic seizures.6
The most prevalent phenotype of the weaver mutation
involves cell death in the central nervous system that
produces a range of neurological dysfunctions. Two
regions of the central nervous system are predominately
affected. In the cerebellum, granule cell neurons die
soon after birth as they fail to differentiate and migrate
into the internal granule cell layer.7 This failure to

Received 4 September 2001; Revised 20 November 2001; Accepted


20 November 2001
Correspondence:
Amy B Harkins, Department of Neurobiology, Pharmacology and
Physiology, The University of Chicago, 947 E. 58th Street, Chicago,
IL 60637, USA.
Tel: +1 773 702 0020. Fax: +1 773 702 3774.
Email: amy@drugs.bsd.uchicago.edu
2002 Martin Dunitz Ltd

Harkins AB, Fox AP.


Cell death in weaver mouse cerebellum
Cerebellum 2002; 1: 201206

migrate appropriately led workers in the eld to postulate that the weaver mutation involved defects in
neuron-glia interactions or other molecular signals
typical of migrating and developing neurons.810 In
mutant mice, large numbers of granule cells are lost2,11
as well as lesser numbers of Purkinje cells12 and neurons
in the deep nuclei of the cerebellum13 producing the
prominent ataxia characteristic of these animals. There
is severe depletion of tyrosine hydroxylase-positive
(dopaminergic) neurons in the substantia nigra resulting
in alterations in locomotion.4,1415 In addition, there are
morphological abnormalities in the hippocampus that
may underlie the seizures.16
In the weaver mouse, the main defect outside of the
central nervous system is reduction in spermatogenesis.
There is decreased sperm motility and degenerative
changes in both mature spermatids and Sertoli cells.17
These defects lead to infertility in male but not female
weaver mouse.5,18

The weaver genetic mutation


Because the weaver granule neurons fail to migrate, the
underlying genetic basis of the mutation was expected to
involve cell-to-cell signaling or other signaling molecules.910 The discovery that the genetic basis of the
weaver mutation was due to the substitution of a serine
for a highly conserved glycine (G156S),19 which altered
the pore region20 of an inwardly rectifying, G-protein
coupled K+ channel, GIRK2 (GIRK2wv) came as a surprise. The glycine that is altered is part of a GYG motif
found in all K+ channels. The mutation of the
GIRK2wv channel results in loss of selectivity for K+
ions allowing Na+ and Ca2+ ions to permeate cells,2125

202

AB Harkins, AP Fox

and these alterations were postulated to play a role in


the disease.
There are at least seven members of this K+ channel
family, GIRK 17 (also designated as Kir3.17). GIRK
channels are coupled to a variety of pertussis toxinsensitive, G-protein linked neurotransmitter receptors
that include adrenergic, muscarinic, purinergic,
dopamine, opioid and GABAB receptors (for recent
reviews, see refs 2628). Channel activation is complicated with G-proteins. Phosphatidylinositol bisphosphate,2932 intracellular Na+,29 ethanol,33,34 and
membrane permeant local anesthetics35 all play a possible role. Typically GIRK channels are believed to be
activated by the subunit of G-proteins (G). These
channels can also be gated by intracellular Na+.29 PIP2
can activate GIRK channels,36 and hydrolysis of PIP2
may be involved in channel desensitization.31 In addition, ethanol appears to open GIRK channels, and
interestingly weaver mutant mice exhibit a loss of
ethanol-induced analgesia.33
Inwardly rectifying K+ channels have two membrane
spanning domains, M1 and M2, that are homologous to
S5 and S6 in voltage-activated K+ channels.3739 Heteromeric GIRK tetramers are believed to assemble to
form functional channels in vivo4042 although the exact
stoichiometry is not known with certainty. GIRK channels are thought to play a critical role in establishing the
resting potential of neurons and cardiac cells as well as
determining the threshold for excitability.4347 GIRK
channels are inwardly rectifying K+ channels that exhibit
increased conductance upon hyperpolarization, and are
believed to clamp the membrane potential near the
equilibrium potential for K+ in excitable and nonexcitable cells.26 Activation of G-protein linked receptors frequently results in simultaneous inhibition of Ca2+
channel currents and activation of GIRK channels48 presumably by direct interaction of G subunits with the
ion channels.4952
Only GIRK 14 are found in mammalian cells. Of
these, only GIRK13 are expressed in brain.21,41,53,54
GIRK3 is exclusively expressed in brain,42,55 whereas
GIRK2 is expressed in brain and testes,19 and GIRK1 is
more widely expressed.55 There is considerable overlap
in the distribution of the three brain isoforms
GIRK1GIRK3.21,42,53,54,56 High levels of GIRK2 are
expressed along with GIRK1 and GIRK3 in the cerebellum, cortex, olfactory bulb, hippocampus, thalamus and
amygdala.53,54,57 Early in development, both GIRK253
and GIRK3 can be detected in the substantia nigra, but
in older mice, GIRK2 predominates.56 In the weaver
mouse, both the cerebellum2,12 and substantia nigra4,14,58
exhibit structural and functional abnormalities; whereas
the hippocampus16 and olfactory bulb59 have cellular
abnormalities without any clear functional consequences. Other regions of the brain that express
GIRK2, such as the thalamus and amygdala, have no
reported abnormalities. Disruption of the GIRK2
channel, as occurs in the weaver mouse, may promote

multiple as yet unknown phenotypes in specic CNS


regions because of the wide distribution of the channel
and the many neurotransmitter receptors to which it
couples.
Native GIRK channels are believed to be comprised
of both GIRK1 and GIRK2 subunits.23,42,60,61 GIRK2
subunits can assemble as homo- or heteromultimers
with other GIRK subunits to form functional channels
when studied in heterologous expression systems41,42
and in heart and brain tissues.62 In expression studies
with oocytes, homomultimers of GIRK2 and heteromultimers of GIRK2 and GIRK1 subunits form K+-selective channels that are activated by G-proteins.41,42 In
comparison to the wild-type subunits, coexpression of
GIRK2wv and GIRK1 subunits results in smaller currents that are non-selective21,23,24 and which may24,25 or
may not21,23 show G-protein regulation.
Coordination of GIRK gene expression and assembly
of different combinations of weaver and wild-type GIRK
subunits may have important functional consequences
in the weaver mutation. For instance, Slesinger et al.
(1997) showed that there are two populations of wildtype granule cells that respond with either slowly- or
rapidly-activating GIRK currents in response to hyperpolarization.63 The slower kinetics are similar to those
reported in oocytes that coexpress both GIRK1 and
GIRK2 heteromultimers;24,41 whereas, the more rapid
kinetics suggest channels made up of homomultimers of
GIRK2 or other combinations of GIRK subunits.63 In a
study in which the endogenous Xenopus GIRK5 was
knocked out by an antisense oligonucleotide, GIRK1
coexpressed with GIRK2wv rescued the weaver phenotype by restoring K+ selectivity and G-protein dependent activation of current.64
Not only do the subunit combinations result in functionally distinct GIRK channels, but the position of
each GIRK subunit within the tetrameric complex has
been shown to play an important role in ion selectivity
and G-protein dependence.65,66 For example, linked
tetrameric channels of GIRK1 and GIRK2wv subunits
joined in either alternating or adjoining patterns of subunits (1-wv-1-wv or 1-1-wv-wv) gave opposite results.
The alternating pattern of subunits formed a K+ selective channel that resembled the coexpressed
GIRK1/2wv channel and the expressed dimer GIRK1GIRK2wv channel.64 In contrast, the adjoining pattern
of subunits formed a non-selective channel that was
similar to the expressed monomeric GIRK2wv
channels.64
Even with all of the accumulated information about
GIRK channels available from a variety of cell and
expression systems, understanding the role of these
channels in cerebellar granule cells has been difcult.
Studies from isolated weaver cerebellar granule cells are
still controversial as to the role of GIRK2wv in cell
death. For instance, Mjaatvedt et al. (1995) did not
observe any GIRK currents in either wild-type or weaver
granule cells;67 whereas other groups have reported

Cell death in weaver mouse cerebellum

GIRK currents in wild-type granule cells.21,67,68 Two


studies of weaver granule cells reported a non-selective
current that was not activated by G-proteins,21,63 yet two
other studies found that weaver neurons lacked a K+
current.67,68 A recent developmental study of GIRK currents recorded in granule cells in the cerebellar slice may
have resolved some of these discrepancies. Rossi et al.
(1998) found that granule cells exhibit different GIRK
currents during pre- and post-migration.69 In wild-type
slices, currents in the pre-migratory granule cells were
G-protein dependent, inwardly rectifying and in postmigratory granule cells, the currents became constitutively-active.69 In contrast, weaver granule cells prior to
migration exhibited a lack of detectable GIRK currents,
but after migration exhibited constitutively-active currents that were similar to expressed mutant subunits.69
These results indicate that GIRK channels expressed in
cerebellar granule cells may be regulated throughout
development.69 Although the granule cell studies make a
denitive mechanism of cell death uncertain, several
possible explanations have been proposed. Two of these
mechanisms are discussed below.

Two possible models for cell death in


weaver cerebellar neurons
Gain of function of the GIRK2 weaver channel
One explanation for the cell death observed in cerebellar
granule neurons is that the weaver defect leads to a constitutively-active GIRK2 channel that is permeable to
both Na+ and Ca2+.21,22 In this model, continuous depolarization, due to the constitutively-active GIRK2wv
channel, results in elevated intracellular Ca2+ levels
which is known to lead to cell death.70 Additionally,
increased Na+ inux via GIRK2wv channels resulting
from a regenerative link between Na+ inux and channel
activation22,71 may compromise metabolic function due
to the energy required to pump Na+ out of cells to overcome the constitutive leak.22 Because cerebellar granule
cells have a small diameter, and hence a high surface-tovolume ratio compared to other neurons, the metabolic
function of these cells may be especially taxed by excessive Na+ removal.
Numerous experimental results support the gain of
function model. First, a non-selective GIRK2wv
channel would result in elevated intracellular Na+ and
Ca2+ concentrations. Resting Ca2+ is elevated in weaver
granule cells compared to wild-type granule cells.7274
Second, increased leak of Na+ and Ca2+ levels result in a
depolarized resting membrane potential in weaver
granule cells compared to wild-type cells.25,68,75 A depolarized membrane potential acts to diminish neuronal
responses to stimulation,73,74 and may activate voltagedependent Ca2+ channels causing a regenerative Ca2+
inux in addition to the regenerative Na+ inux.

203

Further, the weaver mutation has been shown to disrupt


G-protein coupling of the GIRK channel to neurotransmitter receptor function.21 This would result in the
inability of neurotransmitters to activate the inwardly
rectifying K+ current to repolarize cells. Together,
increased resting Ca2+ levels and depolarized membrane
potential could alter differentiation and migration of
granule cells, and also trigger cerebellar granule cell
death (for review, see ref. 76).
By blocking cation inux through the weaver GIRK
channel, weaver granule cell neurons can be rescued
from cell death. Application of QX-314, verapamil, and
MK-801 results in both survival and differentiation of
the weaver granule cells.21,22,74 Other agents that block
Na+ channels (TTX), Ca2+ channels (nifedipine, diltiazem, -conotoxin GVIA), and NMDA receptors
(APV) do not rescue the weaver granule cells suggesting
that the drugs that rescue the weaver neurons do so by
acting on the GIRK2wv channel itself.21,77 In addition,
reducing intracellular Ca2+ with the Ca2+ chelator
BAPTA or preventing Ca2+ entry rescues the weaver
phenotype.7779 QX-314, a Na+ channel blocker, is
thought to act directly on the GIRK2wv channel
because it suppressed the regenerative cation current in
weaver granule cells and blocked non-selective conductance in oocyte experiments.21 In support of this
hypothesis, Slesinger (2001) reported that the mechanism of block by QX-314 is different for non-selective
versus K+-selective GIRK channels.80 In the GIRK2wv
channel, the mutation allows large blocking cations such
as QX-314 to permeate the non-selective pore and reach
a binding site that is typically only accessible from inside
the cell.80
As further support of the gain of function model,
GIRK2 knockout mice exhibit a phenotype that is quite
different than that of the weaver phenotype.61 Specically, GIRK2 knockout mice exhibit no anatomical
anomalies in the brain or other organs. Both the midbrain and cerebellar neurons are morphologically
normal, and the mice are fertile.61 In addition to a lack
of GIRK2 channels in the knockout mice, there is a
reduced expression of GIRK1 channels.61 Unlike weaver
animals, the granule cells isolated from the GIRK2
knockout mice show no constitutively-active GIRK currents. In addition, they exhibit similar in vitro survival
compared to wild-type granule cells.63 These results
strongly suggest that the weaver mutation is due to a
gain of a new toxic GIRK2 function.
Loss of function of the GIRK2 weaver channel
A second mechanism has been proposed to account for
the cerebellar granule cell death observed.67 In this model,
the loss of GIRK2 channel function reduces a major
inhibitory pathway in developing neurons which results in
granule cell hyperexcitability and leads to cell death.67 In
support of this hypothesis, GIRK currents in weaver cerebellar granule neurons are greatly diminished24,68 similar

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AB Harkins, AP Fox

to expression studies in oocytes with GIRK2wv and


GIRK1 subunits.23,24 GIRK1/GIRK2 expression levels
are dramatically decreased60 or not detectable81 in
weaver granule neurons in vivo during the period of neuronal death.
The targeted disruption of the NR1 gene that codes
for the NR1 subunit of the NMDA receptors has
demonstrated that this subunit is necessary for functional NMDA receptors.82 During migration, the precursor granule cells in the cerebellum are exposed to
elevated levels of glutamate which activate NMDA
receptors.83,84 It is believed that this glutamate cue,
along with the subsequent increase in intracellular Ca2+,
signals the cells to migrate and differentiate.76 A lack of
functional GIRK2 channels may result in uncontrolled
depolarization of premigratory cells. In support of this
hypothesis, both in vitro and in vivo granule cell death of
the weaver mutation was rescued by a weaver NR1
double mutant that lacked the NR1 NMDA receptor.85
These results raise the possibility that GIRK2 alone may
not be responsible for the weaver phenotype.
Interestingly, the net effect of the two models for cell
death may be similar. If GIRK2wv channels are constitutively active and leak Na+ or Ca2+ ions21,22 they will
depolarize granule neurons. If the channels are nonfunctional, as suggested by the loss of function
data,24,60,67,68 cerebellar granule cells may be chronically
depolarized as these channels help set the resting potential and make cells less excitable after activation. In each
case, prolonged depolarization of the neurons would
lead to elevation of intracellular Ca2+ levels. As discussed above, the resting membrane potential is depolarized25,68,75 and resting Ca2+ levels are elevated in
weaver granule neurons compared to wild-type cells.7274
Elevation of intracellular Ca2+ levels as a mediator of cell
death is particularly appealing because Ca2+ is a well
characterized trigger for neuronal cell death.70,86,87
Although the GIRK2 point mutation is undoubtedly
associated with the weaver phenotype, several aspects of
the phenotype remain unexplained. In the mouse cerebellum, the weaver phenotype is differentially manifest
in the granule and Purkinje cell neurons. Although
many cells are lost in the weaver cerebellum, cell death
is not complete. Resting Ca2+ is not affected in weaver
Purkinje neurons,72 and both wild-type and weaver

Purkinje neurons express inwardly rectifying K+ currents.81 Because GIRK2 expression does not exhibit any
gradient through the cerebellum,55 there may be additional environmental and/or genetic factors that inuence cell death. This idea is supported by experiments
in which weaver precursor granule cells were rescued
from cell death when mixed with wild-type cells.88 After
the granule cells were mixed, weaver granule cells
extended neurites and migrated suggesting that the premigratory granule cells responded to a local signal and
continued to differentiate.88 In vivo, weaver granule cells
are also rescued from death by environmental cues
following implantation of a wild-type granule cell suspension.10 The mechanisms contributing to the weaver
phenotype could also underlie the apoptotic cell death
and reduced migration of some, but not all granule cell
neurons, and the differential effects on other GIRK2
expressing neurons throughout the brain.

Conclusion
Although the specic mechanism underlying the GIRK2
defect in the weaver mouse is still not resolved, what has
become clear is that certain populations of neurons are
much more susceptible to the defect than are others. In
the granule cells of the cerebellum, both differentiation
and maturation are affected by the genetic defect.
Granule cell neurons die soon after birth as they fail to
differentiate and migrate into the internal granule cell
layer. Interestingly, the cell death observed in Purkinje
neurons that also express the channels is more modest.
Thus, identication of a point mutation in the
GIRK2wv channel as the causative agent leading to
cell death in specic neuronal populations within
both the substantia nigra and cerebellum has
underscored the critical role these channels play
in normal central nervous system development and
function.21,23,60,63,67,69,8991
Acknowledgement
We are thankful to Dr Lisa Won for reading the manuscript.

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