Behavioral effects of neonatal lesions on the cerebellar system

Int. J. Devl Neuroscience 43 (2015) 58–65

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International Journal of Developmental Neuroscience journal homepage: www.elsevier.com/locate/ijdevneu

Behavioral effects of neonatal lesions on the cerebellar system Robert Lalonde a,∗ , Catherine Strazielle b a

Université de Rouen, Département Psychologie, Laboratoire ICONES EA 4699, 76821 Mont-Saint-Aignan Cedex, France Université de Lorraine, Laboratoire “Stress, Immunité, Pathogènes” EA 7300, and Service de Microscopie Electronique, Faculté de Médecine, 9 avenue de la Forêt de Haye, and CHU de Nancy, 54500 Vandoeuvre-les-Nancy, France b

a r t i c l e

i n f o

Article history: Received 26 January 2015 Received in revised form 4 April 2015 Accepted 13 April 2015 Available online 20 April 2015 Keywords: Cerebellum Cerebellar mutants Motor coordination Purkinje cells Granule cells Paw-clasping X-Irradiation SHIRPA Body righting Rotorod Stationary beam Wire suspension

a b s t r a c t Several rodent models with spontaneous mutations causing cerebellar pathology are impaired in motor functions during the neonatal period, including Grid2Lc , Rorasg , Dab1scm , Girk2Wv , Lmx1adr -sst , Myo5adn , Inpp4awbl , and Cacna1arol mice as well as shaker and dystonic rats. Deficits are also evident in murine null mutants such as Zic1, Fgfr1/FgFr2, and Xpa/Ercc8. Behavioral deficits are time-dependent following X-irradiated- or aspiration-induced lesions of the cerebellum in rats. In addition, motor functions are deficient after lesions in cerebellar-related pathways. As in animal subjects, sensorimotor disturbances have been described in children with cerebellar lesions. These results underline the importance of the cerebellum and its connections in the development of motor functions. © 2015 Elsevier Ltd. All rights reserved.

1. Specificity of cell growth in the cerebellum The effects of lesions of the cerebellum or associated brain regions during the neonatal period in rodents (from the day of birth to weaning on postnatal day 21) provide information as to the functional impact of cell growth processes. Various behavioral effects are obtained depending on the postnatal day the lesions were made or their effects evaluated. In the rat, the cerebellar deep nuclei, Purkinje cells, and Golgi cells are formed on embryonic days 13 and 14, 14 and 15, and 19 up to the perinatal period, respectively (Altman and Bayer, 1978). Granule, basket, and stellate cells of the cerebellar cortex are formed from birth until day 21, on postnatal days 7 and 8, and on postnatal days 8–11, respectively (Altman, 1969, 1972). Besides cell birth, a possible source of behavioral variability in lesion effects is the change occurring regarding synaptic contacts. For example, rat Purkinje cells are polyinnervated by climbing fibers up to postnatal day 15 but then become mostly monoinnervated (Delhaye-Bouchaud et al., 1978; Mariani et al.,

∗ Corresponding author. Tel.: +33 2 35 14 61 08; fax: +33 2 35 14 63 49. E-mail address: [email protected] (R. Lalonde). http://dx.doi.org/10.1016/j.ijdevneu.2015.04.007 0736-5748/© 2015 Elsevier Ltd. All rights reserved.

1990). Manto and Jissendi (2012) reviewed the molecular aspects of cerebellar development, including the importance of the Math1 gene, encoding a transcription factor crucial in the development of glutamatergic neurons, as well as Ptf1a, encoding a transcription factor crucial in the development of neurons containing gammaaminobutyric acid (GABA). 2. Behavioral effects of neonatal cerebellar lesions in rodents 2.1. Spontaneous mutants 2.1.1. Grid2Lc mutant mouse The neuropathology of the autosomal semi-dominant Lurcher mutation is caused by a gain-in-malfunction of the Grid2 gene located on chromosome 6 and encoding an ionotropic glutamate receptor predominantly expressed on Purkinje cells (Zuo et al., 1997). While homozygous Grid2Lc mutants die early because of defective suckling caused by brainstem damage (Resibois et al., 1997), the heterozygous can be evaluated throughout development and also as adults. The increased permeability of the mutated glutamate channel to calcium (Wollmuth et al., 2000) is likely

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responsible for the nearly complete degeneration of Purkinje cells occurring from the second to the fourth postnatal week (Caddy and Biscoe, 1979), at a time when such cells develop dendritic arbors and spines for synaptic contacts (Hatten and Heintz, 1995). The massive degeneration of granule cells is attributed to the loss in the trophic influence exerted by Purkinje cells on them (Vogel et al., 1991). Likewise, the 60–75% decrease in inferior olive cell number (Caddy and Biscoe, 1979; Heckroth and Eisenman, 1991) and the 30% decrease in deep cerebellar nuclei number (Heckroth, 1994) are secondary consequences of Purkinje cell atrophy, causing retrograde and anterograde degeneration, respectively. The overall neuropathology leads to early-onset cerebellar ataxia and deficits in motor coordination (Lalonde et al., 1996). Grid2Lc mutants were evaluated from postnatal days 0 (day of birth) to 30 in the following tests: body righting from a supine position on the back (days 0–30), negative geotropism up an inclined grid (days 0–15), motor coordination on rotating grid (days 11–14), wire suspension (days 6–16), and rotorod (days 0–30) tests, as well as swimming toward and grabbing a vertical pole (days 22–30) (Thullier et al., 1997). Wire suspension began on day 6 since the start of a potent grasping response was seen in normal mice only on day 7 (Fox, 1965). Moreover, swimming toward a vertical pole cannot reasonably be started before the eyes open on day 11. Relative to wild-type, body righting and negative geotropism were observed at their normal times in Grid2Lc mutants. Indeed, body righting became prominent in both groups on day 5, as noted previously in normal mice of another strain (Fox, 1965). However, the mutants took longer to right themselves from days 13 to 30. In contrast, the mutants turned upward more quickly than controls on the inclined grid, presumably because of a lack in postural stability. Indeed, the mutants showed poorer motor coordination in all three tests: rotating grid (days 11–14), wire suspension (days 15 and 16), and rotorod (days 14–30). A summary of these results is provided in Table 1. As Dufour-Mallet et al. (1979) noted in mice and Bâ and Seri (1995) in rats, latencies before falling from each apparatus increased sharply in our wild-type strain. Relative to wild-type, the mutants also had slower visuomotor responses before swimming to the vertical pole throughout the testing period. 2.1.2. Rorasg mutant mouse The autosomal recessive staggerer mutation causes a deletion of the Rora gene located on chromosome 9 (Hamilton et al., 1996). This gene encodes retinoic acid-related orphan receptor, a transcription factor involved in neuronal differentiation and maturation, highly expressed in Purkinje cells (Hamilton et al., 1996; Ino, 2004; Nakagawa et al., 1997; Sashihara et al., 1996), and belonging to the steroid/thyroid hormone receptor superfamily (Koibuchi, 2008, 2013). In Rorasg homozygotes, Purkinje cells declined in number before postnatal day 5 and, at the end of the first month, only 25% of them remained (Herrup and Mullen, 1979). Thus, the Purkinje cell loss begins earlier than Grid2Lc mutants (postnatal day 8) but is less complete (Caddy and Biscoe, 1979). Because of its earlier start, the Rorasg + Grid2Lc double mutant possesses the Rorasg phenotype in terms of cell degeneration (Messer et al., 1991). The granule cell loss in Rorasg mutants is secondary to Purkinje cell degeneration, begins soon after their migration (Herrup, 1983), and is nearly total by the end of the first postnatal month (Landis and Sidman, 1978). Despite the Purkinje cell loss, the deep cerebellar nuclei appear present in normal numbers (Roffler-Tarlov and Herrup, 1981). However, presumably because of Purkinje cell loss, the number of inferior olive neurons decreased by 60% as early as postnatal day 24 (Shojaeian et al., 1985). Unlike the one-to-one contact seen in normal mice, Purkinje cells are multiply innervated by climbing fibers in the mutant, a sign of developmental arrest (Mariani, 1982). The overall neuropathology leads to early-onset cerebellar ataxia and deficits in motor coordination (Lalonde et al., 1996).

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Table 1 Behavioral characteristics of cerebellar mutants. Mutant and nature of cerebellar cell loss

Behavioral characteristics

Grid2Lc mutant mouse Purkinje and granule cells Rorasg mutant mouse Purkinje and granule cells Dab1scm mutant mouse Granule cells Girk2Wv mutant mouse Granule cells Lmx1adr -sst mutant mouse Irregular pattern of foliation Myo5adn mutant mouse Smaller with intact foliation pattern Inpp4awbl mutant mouse Purkinje cells Cacna1arol mutant mouse Reduced calcium channel voltage Shaker mutant rat Purkinje cells Dystonic mutant rat Increased noradrenergic levels Zic1 null mutant Hypoplasia and missing anterior lobe Fgfr1/FgFr2 double null mutant Dispersed granule cells Xpa/Ercc8 double null mutant Impaired foliation

Ataxia, impaired body righting and motor coordination Ataxia, impaired body righting and motor coordination Ataxia, impaired drop-righting, negative geotaxis, and motor coordination Ataxia, impaired swimming and grooming Ataxia, impaired body righting and motor coordination Ataxia, impaired eyeblink conditioning and motor coordination Ataxia Ataxia, impaired body righting, negative geotaxis, and motor coordination Ataxia, impaired body righting Ataxia, impaired motor coordination

Ataxia

Ataxia, impaired motor coordination

Ataxia

Rorasg mutants were compared to non-ataxic controls from postnatal days 1 to 9 in body righting and cliff aversion tests (Heuzé et al., 1997). The body righting of Rorasg mutants was slower than that of controls on postnatal days 7–9. Although Grid2Lc mutants also showed slower body righting responses, this occurred later in development, from postnatal days 13 to 30 (Thullier et al., 1997), presumably because of their later onset of Purkinje cell degeneration (Messer et al., 1991). In addition, more Rorasg mutants fell off a cliff on postnatal day 7, probably as a result of motor instability. Male mutants were next evaluated for motor control involved in mating during the adult period after receiving vestibular stimulation from postnatal days 1 to 21 (Guastavino et al., 1993). Mouse pups placed on a tilting turntable from 5 min to 30 min per day were better able to mate than non-stimulated controls. 2.1.3. Dab1scm mutant mouse The autosomal recessive scrambler mouse is mutated for the Dab1 gene located on chromosome 4, which causes a deficiency in disabled-1, involved in reelin signaling (Rice et al., 1998; Sweet et al., 1996). As a result, homozygous Dab1scm mutants possess a loss-of-function reeler-like phenotype characterized by cell malposition in cerebellar cortex, hippocampus, and neocortex (Gonzalez et al., 1997; Rice et al., 1998; Sheldon et al., 1997; Sweet et al., 1996; Weiss et al., 2003). As seen in the previous mutants, Purkinje and granule cell degeneration in Dab1scm mutants results in early-onset ataxia and deficits in motor coordination (Jacquelin et al., 2012). Dab1scm mutants were compared to non-ataxic controls in a neurologic screen, the SmithKline Beecham, Harwell, Imperial College, Royal London Hospital, phenotype assessment (SHIRPA) from the day of birth to postnatal day 22 (Jacquelin et al., 2012). An abnormal gait and body tremors were detected as early as postnatal day 8. On day 15, negative geotaxic responses were incomplete and slow, the drop righting reflex was impaired, and motor coordination was

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deficient along with a deficit in grip strengh. On day 22, more neurologic signs appeared, including longer freezing times when first exposed in a 1 min open-field test and fewer squares traversed. However, as adults, their phenotype converted to hyperactivity in a 5-min open-field test (Jacquelin et al., 2013). 2.1.4. Girk2Wv mutant mouse The autosomal semi-dominant Weaver mutation comprises a base pair substitution of an inward rectifying K+ channel strongly expressed in cerebellum and ventral midbrain (Patil et al., 1995). Since no cerebellar pathology occurs in Girk2 knockout mice (Signorini et al., 1997), Girk2Wv is deemed a gain-in-malfunction mutation. In normal adult mouse brain, Girk2 mRNA and protein levels were detectable in cerebellar granule and Purkinje cells as well as substantia nigra pars compacta, ventral tegmentum, and olfactory tubercle (Schein et al., 1998), all regions degenerating in the mutant. In the cerebellum, the main depletion occurs in the granule cell (Hirano and Dembitzer, 1973), direct target of the mutated gene (Goldowitz and Mullen, 1982). Unlike the loss in post-migratory granule cells found in Grid2Lc (Wetts and Herrup, 1982) and Rorasg (Herrup, 1983), the Girk2Wv granule cell decrement is mostly pre-migratory. Indeed, dying pyknotic cells increased in the external granule cell layer as early as the day of birth, prior to their migration to the internal granule cell layer beginning on postnatal day 4 in the normal mouse (Smeyne and Goldowitz, 1989). The loss in Purkinje cells is more limited than that of granule cells, though the remaining neurons are found in ectopic positions (Blatt and Eisenman, 1985). Unlike cerebellar mutants with more severe Purkinje cell loss, particularly Grid2Lc (Caddy and Biscoe, 1979) and Rorasg (Shojaeian et al., 1985), and to a lesser extent Relnrl (reeler) (Blatt and Eisenman, 1985; Shojaeian et al., 1985), the number of inferior olive neurons was maintained in Girk2Wv mutants (Blatt and Eisenman, 1985). Nevertheless, like Rorasg and Relnrl , Girk2Wv Purkinje cells are innervated by multiple climbing fibers as opposed to the monoinnervation prevalent in normal mice (Mariani, 1982). In addition to the cerebellum, cell death in Girk2Wv homozygotes was observed in dopaminergic neurons of the substantia nigra pars compacta and to a lesser extent the ventral tegmentum (Triarhou et al., 1988), mainly between the second and fourth postnatal week (Roffler-Tarlov et al., 1996). As a result of these pathologies, the mutants are characterized by early-onset ataxia and a loss in motor coordination (Lalonde, 1987). Girk2Wv mutants were compared to non-ataxic controls in swimming activity during weaning (Bolivar et al., 1996). On postnatal day 3, fewer Girk2Wv mutants were able to swim than controls. Moreover, the mutants were unable to display forelimb swimming movements on day 5, though not on day 9. The mutants were also characterized by longer forelimb stroke durations and stroke cycle onset. In addition, Girk2Wv mutants were compared to non-ataxic controls on postnatal days 13–20 on grooming activity after their swim (Coscia and Fentress, 1993). The mutants exhibited a greater number and shorter durations of grooming bouts as well as fewer elements per bout. These results indicate a role for the cerebellum or basal ganglia on the motor sequences underlying swimming and grooming. 2.1.5. Lmx1adr -sst mutant mouse Several mutations of the Lmx1a gene encoding LIM homeobox transcription factor 1 alpha have been described, including shaker short-tail (sst), an allele of dreher (dr) (Wahlsten et al., 1983) located on chromosome 1 (Bergstrom et al., 1999). Lmx1adr -sst mutant mice are inherited as a single autosomal recessive gene marked by an irregular pattern of foliation in the cerebellum, body swaying, and a short or blunt tail (Wahlsten et al., 1983). Examination over postnatal days 6, 8, and 10 revealed impaired body righting, cliff aversion,

screen climbing, and bar-grasping responses in Lmx1adr -sst mutants relative to non-ataxic controls (Lyons and Wahlsten, 1988). 2.1.6. Myo5adn mutant mouse Several Myo5a mutations have been described, encoding myosin VA, which include the autosomal recessive dilute-neurological (dn) allele located on chromosome 9 (Huang et al., 1998). Myo5adn mutants showed signs of ataxia on postnatal day 11 and are characterized by a smaller cerebellum though with an intact foliation pattern (Miyata et al., 2011). Likewise, ataxia was detectable as early as postnatal day 7 in the dilute-lethal allele, Myo5adl (Sawada et al., 1999). There was a reduction in smooth endoplasmic reticulum and inositol-3 phosphate receptors on the spines of Purkinje cells in Myo5adn mutants. Myo5adn mutants were trained on eyeblink conditioning on postnatal days 17–19, 28–29, and 60 as well as stationary beam and rotorod tests on postnatal days 26–29 and 60–63 (Miyata et al., 2011). Relative to non-ataxic controls, the mutants were impaired on eyeblink conditioning on postnatal days 17–19 but not later, whereas their impairment on the two motor coordination tests occurred during both periods of evaluation. These results indicate different time windows in the involvement of the cerebellum on eyeblink conditioning as opposed to motor coordination. 2.1.7. Inpp4awbl mutant mouse The weeble mouse is an autosomal recessive mutation affecting the Inpp4a gene located on chromosome 1 and encoding inositol polyphosphate 4-phosphatase type I (Nystuen et al., 2001). Inpp4awbl mutants usually die within a month, probably from generalized seizures. On postnatal day 8, the cerebellum of the homozygotes is smaller but folia and cortical layers appear normal. Progressive Purkinje cell loss occurs from postnatal days 6 to 12 and, unlike controls, terminal deoxynucleotidyl transferase dUTP nick end labeled granule cells are evident, a sign of ongoing degeneration. Inpp4awbl mutants have been described as ataxic by postnatal day 14 but have not been further tested. 2.1.8. Cacna1arol mutant mouse Rolling mouse Nagoya is an autosomal recessive mutation affecting the Cacna1a gene located on chromosome 8 and encoding the calcium channel voltage-dependent P/Q type alpha 1A subunit (Mori et al., 2010). Cacna1arol mutants displayed reduced voltage of this channel on Purkinje cells (Mori et al., 2010), leading to ataxia, motor coordination deficits, and muscle weakness (Kaja et al., 2007; Plomp et al., 2009). Cacna1arol mutants were compared to non-ataxic controls once every second day on the following tests: body righting (postnatal days 0–22), negative geotaxis (postnatal days 2–22), hindlimb suspension (postnatal days 0–14), and the presence of the abnormal hindlimb-clasping reflex occurring during tail suspension (postnatal days 0–22) (Takahashi et al., 2010). Body righting and negative geotaxic responses were impaired in Cacna1arol mutants on postnatal days 14–22 and were slower on postnatal days 8–22. As mentioned above, slow body righting is a characteristic of Grid2Lc (Thullier et al., 1997) and Rorasg (Heuzé et al., 1997) mutants. However, Grid2Lc mutants with more severe cerebellar pathology than Cacna1arol were faster than their wild-type controls in negative geotaxic responses (Thullier et al., 1997), indicating a reversed phenotypic expression. Latencies before falling from hindlimb suspension were lower in Cacna1arol mutants than controls on postnatal days 8–14, indicating muscle weakness. In addition, hindlimb-clasping was more frequent on postnatal days 14–22, a response seen in Rorasg and Dab1scm though not in Grid2Lc mutants (Lalonde and Strazielle, 2011).

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Cacna1arol mutants were also examined on postural control underlying hindlimb support, rope descent, narrow path traverse, locomotion along an inclined corridor, and swimming (Tamaki et al., 1986). Until the second week of age, Cacna1arol mutants developed primitive responses similar to though somewhat slower than controls, but failed to show mature movements on postnatal days 16–18 during hinblimb support, rope descent, and swimming. In particular, the mutants were characterized by head-up descent in contrast to the normal head-down descent and an inconsistent use of hindlimb paddling while swimming. 2.1.9. Shaker mutant rat Shaker mutant rats are characterized by a semi-dominant chromosome X-linked mutation of an unknown gene (Clark et al., 2000), leading to Purkinje cell degeneration and ataxia (Tolbert et al., 1995). When tested on postnatal day 4, shaker mutant rats were marked by a delay in body righting, though normal values were attained on day 10 (Wolf et al., 1996). On the contrary, there was no intergroup difference in negative geotropism, mid-air righting, or cliff avoidance tests. 2.1.10. Dystonic mutant rat A dystonic rat inherited in an autosomal recessive pattern of an unknown gene has been tested during developmental stages (Lorden et al., 1984). The dt mutants are characterized by increased noradrenergic levels in the cerebellum in the 16–25 postnatal day interval (Lorden et al., 1984) and increased activity of glutamic acid decarboxylase, the GABA-synthesizing enzyme, in the deep cerebellar nuclei on postnatal day 20 (Oltmans et al., 1986). They are behaviorally characterized by paw-clasping while still on the ground, twisting responses, and frequent falls. On postnatal days 9–12, dt mutant rats displayed reduced climbing ability relative to controls (Lorden et al., 1984). The dt mutants were next evaluated for motor control on postnatal day 20 following lesions in either deep cerebellar or lateral vestibular nuclei made on day 15 (LeDoux et al., 1995). Electrolytic lesions of either region decreased paw-clasping and twisting responses, falls, and body righting latencies. These data indicate that dysfunctional neurons in the two regions cause worse neurologic deficits than when they are destroyed. 2.2. Induced mouse mutations 2.2.1. Zic1 null mutant The Zic1 gene located on chromosome 3 is highly expressed in the cerebellum during development (Aruga et al., 1996). Zic1 null mutants are characterized by cerebellar hypoplasia and a missing anterior lobe (Aruga et al., 1998). In the prenatal stage, there is a loss in proliferating cells of the external germinal layer. The mutant homozygotes displayed ataxia and paw-clasping responses on postnatal day 14 and most died within a month (Aruga et al., 1998). Non-ataxic heterozygotes tested at 3 months of age exhibited motor coordination deficits relative to wild-type on stationary beam and wire-hanging tests (Ogura et al., 2001). 2.2.2. Conditional Fgfr1/FgFr2 double null mutant Fgfr1 and FgFr2 genes located on chromosomes 8 and 10, respectively, and encoding fibroblast receptors 1 and 2, are highly expressed in Purkinje cells (Lin et al., 2009). Conditional Fgfr1/FgFr2 double null mutants caused less well-marked foliations in all three layers of the cerebellar cortex and dispersed granule cells on postnatal day 14 (Müller Smith et al., 2012). Fgfr1/FgFr2 null mutants have an ataxic gait and were impaired on the rotorod test of motor coordination on postnatal day 35.

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2.2.3. Xpa/Ercc8 double null mutant A double null mutation has been generated regarding the Xpa gene found on chromosome 4 and encoding xeroderma pigmentosum complementation group A as well as the Ercc8 gene found on chromosome 13 and encoding excision repair crosscomplementing rodent repair deficiency complementation group 8, associated with Xeroderma pigmentosum and Cockayne syndrome, respectively, both autosomal recessive disorders with a defect in the nucleotide excision repair pathway required for removing DNA damage (Murai et al., 2001). Xpa/Ercc8 null mutants are characterized by impaired foliation and sulcus formation throughout the cerebellum. All three cerebellar cortical layers appear thinner and Purkinje cell dendrites more stunted than normal during the first two postnatal weeks. Signs of ataxia appeared on postnatal day 7 and became more prominent one week later. When suspended by the tail, the double knockout exhibited pawclasping responses seen in other cerebellar mutants (Lalonde and Strazielle, 2011). 2.3. Lesion-causing irradiation by X-rays in rats Irradiation by X-rays has a neurotoxic action strictly on cells being generated. The effects of X-irradiation on rat behavior have been examined at different stages of postnatal cerebellar development (Pellegrino and Altman, 1979). Rat pups were exposed to X-irradiation on postnatal days 4 and 5 (4–5X) or days 8, 9, 11, 13, and 15 (8–15X) and tested for motor coordination (Table 2). The 4–5X rats have a 60% loss in granule cells while basket and stellate cells are present but disorganized. The 8–15X rats have a 80% loss in granule cells while stellate cells are absent and basket cells are preserved and organized. Relative to unexposed controls matched for age, 2-month-old 4–5X but not 8–15X rats were impaired in crossing a rotorod for food reward. When rats were tested in the open-field test of locomotion as infants (third postnatal week) or juveniles (2 months old), two groups were added: 4–15X rats with an almost complete loss in granule, basket, and stellate cells as well as 12–15X rats with only granule cells missing (40% loss). When tested as infants or juveniles, only 4–15X and 4–5X groups crossed fewer squares than controls. The juvenile 12–15X group crossed more squares than age-matched controls, whereas no change occurred in the 8–15X group at either age. The hypoactivity of early-lesioned groups is reminiscent of the Rorasg mutant with early-onset degeneration of the cerebellar cortex (Lalonde et al., 1988), whereas the hyperactivity of the late-lesioned group is reminiscent of Grid2Lc (Lalonde et al., 1986) and Dab1scm (Jacquelin et al., 2013) mutants with later onset degeneration of the cerebellar cortex. The same X-irradiated rats were evaluated in two multiple-unit water mazes. The 4–5X, 4–15X, and 12–15X groups were slower in acquiring at least one of the maze routes, whereas the 8–15X group was not, although all lesioned groups had equivalent swimming speeds relative to controls. Thus, in all three tests, the 8–15X group was the only one spared, presumably because of relatively intact inhibitory neurons relative to the earlier lesioned groups. Their better scores relative to the 12–15X group seem paradoxical, but may eventually be explained by an as yet unidentified compensatory process. Table 2 Behavioral characteristics of X-irradiated rats. Type

Behavioral characteristics

4–5X 8–15X 4–15X 12–15X

Impaired motor coordination and maze learning, hypoactivity Normal motor coordination, maze learning, and locomotor activity Impaired maze learning, hypoactivity Impaired maze learning, hyperactivity

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In further studies, 5–14X and 10–14X groups were compared to non-exposed controls on the rotorod (Le Marec et al., 1997a) and spatial learning in a water maze test with constant starting positions (Le Marec et al., 1997b). The early-lesioned but not the late-lesioned group is characterized by many polyinnervated Purkinje cells by climbing fibers (Delhaye-Bouchaud et al., 1978; Mariani et al., 1990). The acquisition of motor and spatial tasks was slower in both X-irradiated groups than controls, but only the late-lesioned group was able to reach the same level of asymptotic performance as controls. In contrast to their deficient spatial learning, 5–14X rats (10–14X rats were left untested) performed normally in the visible platform subtask. Likewise, lesions of the inferior olive caused by 3-acetylpyridine combined with niacinamide injected on postnatal day 15 slowed down the acquisition of the rotorod task starting on day 23 (Jones et al., 1995). The poorer scores of the 5–14X group may be caused by polyinnervation of Purkinje cells by climbing fibers (Delhaye-Bouchaud et al., 1978; Mariani et al., 1990). Moreover, deficits on rotorod and spatial learning tasks with sparing of the visible platform subtask occurred in 5–14X rats receiving acetylpyridine and niacinamide on postnatal day 15 and tested at 3 months of age (Rondi-Reig et al., 2002). 2.4. Aspiration or electrolytic lesions in rats In addition to X-irradiation, motor coordination has been evaluated in rats cerebellectomized during various stages of postnatal development (Auvray et al., 1989; Zion et al., 1990). Rat pups cerebellectomized by aspiration on postnatal days 10, 15, 20, and 24 were trained every day starting on the day after the operation and tested on the rotorod. Pups cerebellectomized on days 10 and 15 had severe impairments relative to unoperated controls and were unable to reach their asymptotic level of performance, whereas pups cerebellectomized on days 20 and 24 succeeded in reaching this asymptote. As was the case with X-irradiation, the poorer scores of the early-lesioned groups may be due to the polyinnervation of Purkinje cells by climbing fibers (Delhaye-Bouchaud et al., 1978; Mariani et al., 1990). Other experimenters have focused on the behavioral consequences of hemicerebellectomy. In one study, rats were hemicerebellectomized from the day of birth and tested throughout the weaning period (Petrosini et al., 1990). Relative to sham-operated controls, hemicerebellectomized rats were developmentally delayed in body righting as well as turning on an inclined grid. These results differ from those found in Grid2Lc mutants that were not delayed on either measure (Thullier et al., 1997), probably due to the later onset of Purkinje cell degeneration in the mutants. In contrast, the results found in hemicerebellectomized rats regarding motor coordination resembled those of Grid2Lc mutants in that the rats were deficient in stationary beam, wire suspension, and ladder-climbing tests. Relative to sham controls, hemicerebellectomized rats also had delayed maturation of vestibular-controlled dropping responses. On the contrary, there were no intergroup differences in visual or propioceptive placing reflexes and head, shoulder, or pelvis elevation. In a second study, neonatally lesioned rats exhibited more difficulty than adult-lesioned rats in using their hindlimbs while suspended from a wire (Molinari et al., 1990), as were Cacna1arol mutant mice (Takahashi et al., 2010; Tamaki et al., 1986). An electrophysiological measure of heightened susceptibility was demonstrated in hemicerebellectomized rats during development as opposed to the adult period (O’Donoghue et al., 1986). After electrical stimulation of the motor cortex, ipsilateral limb movements were evoked at lower thresholds in rats hemicerebellectomized on postnatal days 2, 10, and 21 than in

those hemicerebellectomized as adults Thus, hemicerebellectomy modified the electrophysiological properties of the corticospinal tract more readily during the first three postnatal weeks, which may account for lesion-induced compensatory processes seen in behavioral studies. The classically conditioned eyelid response was studied in 24day-old rats after ipsilateral or contralateral aspiration lesions of the cerebellar cortex and deep nuclei on postnatal day s 10 or 20 (Freeman et al., 1995). An auditory stimulus served as the conditioned stimulus and electric impulses applied around the eye as the unconditioned stimulus, leading to conditioned blinking. The operated groups exhibited a normal response to the unconditioned stimulus. In contrast, the acquisition of the eyelid response was slower than unoperated controls in rats lesioned either ipsilaterally or contralaterally to the trained eye on postnatal day 10, whereas those lesioned on day 20 were slowed down only ipsilaterally to the trained eye. The ipsilateral defect on either postnatal day was identical to that found in adult rabbits, indicating a matured response by postnatal day 10, whereas the contralateral defect on day 10 is temporary, not seen on either postnatal day 20 or adults (Lavond and Steinmetz, 1989; Lincoln et al., 1982), indicating a matured response on postnatal day 20. Classically conditioned bradycardia was studied in 3-month-old rabbits after electrolytic lesions of the cerebellar vermis on postnatal days 5 or 18 (Ghelarducci et al., 1996). An auditory stimulus served as the conditioned stimulus and electric impulses applied to the ear as the unconditioned stimulus, leading to conditioned bradycardia. Both operated groups exhibited a normal baseline heart rate. In contrast, the amplitude of conditioned bradycardia was lower than unoperated controls in rabbits lesioned on day 18 but higher than unoperated controls in rabbits lesioned on day 5. The results on postnatal day 18 were similar to those found in adult rabbits (Sebastiani et al., 1992; Supple and Kapp, 1993; Supple et al., 1993) and adult rats (Supple and Leaton, 1990), indicating maturation of the cerebellar system at this stage, whereas an exaggerated compensatory response was obtained in rabbits lesioned on postnatal day 5.

3. Behavioral effects of neonatal lesions on cerebellar circuits in rodents 3.1. Motor cortex Experiments have been conducted concerning lesioning afferent and efferent structures to the cerebellum. Rats with bilateral lesions of the motor cortex on postnatal day 4 and tested as adults had worse stationary beam performances than those lesioned and tested as adults (Kolb and Holmes, 1983). In addition, neonatally lesioned rats had worse difficulty in swimming efficiently as measured by the forepaw inhibition response. Moreover, unlike adult rats, neonatally lesioned rats were impaired during spatial learning of the Morris water maze, attributed to thinning in other neocortical areas as a secondary consequence of the main lesion. In contrast, neonatally lesioned rats were better than lesioned adults in manipulating food pellets and both groups were equally impaired in tongue extension and latch-box puzzles. Thus, age-related effects were task-specific, early-lesioned rats being generally more vulnerable, but sometimes less vulnerable, as was the case in the following study. Rats with unilateral lesions of the motor cortex on the day of birth and tested 4 months afterwards had better scores in reaching between bars for food pellets in the contralateral limb than adults with the same lesions (Whishaw and Kolb, 1988). In contrast, the ipsilateral limb was equally impaired in both groups relative to sham-operated controls.

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3.2. Brainstem and thalamus In further experiments on cerebellar-related pathways, weanling rats were lesioned on postnatal days 21–28 and tested about three weeks later. Electrolytic lesions of the pontine reticular formation slowed down the acquisition of a detour task whereby rats were forced to dig inside a sandbox before reaching a goal box filled with food (Thompson et al., 1989c). The same deficits occurred when hungry rats were confronted with a platform, a cylinder, or a ladder (Thompson et al., 1989b). These results were interpreted as problem-solving as opposed to motor impairments, because the appropriate motor responses appeared as well coordinated as those of controls. Moreover, no deficit occurred on a stationary beam task whereby rats were observed for possible falls during 5 s of testing on progressively narrower beams (Thompson et al., 1989b). Lesions of the pontine reticular formation as well as the ventrolateral thalamus slowed down the acquisition of puzzle-box learning whereby animals were forced to push, pull, or unlock latches to obtain food (Thompson et al., 1989a). Likewise, ventrolateral thalamic lesions in weanling rats caused deficits in juvenile rats tested in detour learning (Thompson et al., 1989b,c) and puzzle-box learning (Thompson et al., 1989a) tasks. Lesion effects are not limited to tasks with an important motor component. Indeed, electrolytic lesions in either pontine reticular formation or ventrolateral thalamus of weanling rats tested as juveniles slowed down the acquisition of black-white discrimination learning in a water basin (Thompson et al., 1989b). Acquisition was also retarded after either lesion in a shock avoidance matching-tosample task. Likewise, lesions of the pontine reticular formation slowed down the acquisition of other shock avoidance tasks, namely a 3-unit maze requiring left–right turns and two nonspatial discrimination tasks, one visual (black–white) and the other kinesthetic (inclined plane) (Thompson et al., 1984, 1986). Moreover, the same lesions slowed down the acquisition and extinction of a straight runway task for water reward (Thompson et al., 1985). In contrast, lesions of the ventromedial thalamus slowed down the acquisition of the 3-unit maze and the inclined plane but not the visual discrimination task (Thompson et al., 1987).

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lar cell types on autistic-like behavior has been reviewed (Maloney et al., 2013). In a similar manner to autistic subjects, a selective attention disorder in the form of impaired shifting between auditory and visual stimuli was observed after acquired cerebellar lesions (Courchesne et al., 1994). Steinlin et al. (2003) presented follow-up data from patients operated during childhood for benign cerebellar tumors. Marked problems in selective attention were present but only in a minority of them. There is also neuropsychological and imaging evidence that alterations in the cerebellum and its connections with the prefrontal cortex are involved in attention-deficit/hyperactivity disorder (Arnsten, 2006). The influence of cerebellar damage on language is more uncertain and debatable. Although surgery to treat midline posterior fossa neoplasm in children by removing the vermis often causes acute mutism (Riva and Giorgi, 2000; Turkel et al., 2004), particularly when the fastigial nuclei are affected (Ozimek et al., 2004), the mutism resolves spontaneously (Liu et al., 1998). Richter et al. (2005b) studied children who had undergone surgery for cerebellar astrocytoma without subsequent radiation- or chemo-therapy and found no persistent language disorder. 5. Concluding remarks There is a need to standardize testing of mutant and experimentally lesioned animals during the development period, as no model has yet been evaluated with the same methodology except for isolated tests such as body righting and negative geotaxis. Experimental lesions on specific postnatal days provide complementary data to those of mutations, and therefore, might be compared in the same study. A complementary approach would give us a better understanding on the functional impact of cerebellar-related dysfunctions during development which could be extended to human beings. Acknowledgment Funding was provided by French Agencies governing our laboratories in Rouen and Nancy.

4. Behavioral effects of cerebellar lesions in children References As in animal subjects, sensorimotor disturbances have been described in children with cerebellar lesions. Neonatal cerebellar lesions cause developmental delays in psychomotor functions (O’Shea et al., 2008). Balance problems after surgery of a benign cerebellar tumor were more likely when lesions involved fastigial and interpositus nuclei (Schoch et al., 2010). Young subjects with cerebellar lesions are also subject to cognitive and emotional disturbances. Children who had undergone surgery for cerebellar astrocytoma without subsequent radiation- or chemo-therapy had increased anxious or aggressive behavior (Richter et al., 2005a). Moreover, cerebellar hypoplasia increased the occurrence of epilepsy, mental retardation, and neuropsychiatric disorders (Parmeggiani et al., 2003). The most studied neuropsychiatric disorder in this context concerns autisticlike symptomatology. Cerebellar lesions often cause mutism and dysarthria, symptoms seen in the autistic spectrum disorder (Tasdemiro˘glu et al., 2011). Indeed, bilateral cerebellar lesions increased the likelihood of autistic symptomatology (Eluvathingal et al., 2006). In children with cerebellar vermis malformation, social communicative skills were affected (Tavano et al., 2007). Moreover, vermal lesions in children who had undergone surgery to treat cerebellar hemispheric or vermis tumors or viral cerebellitis in another child led to emotional disturbances from irritability to an autistic response (Riva and Giorgi, 2000). The possible influence of cerebel-

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