Loss Of Dentate Granule Cells Research Articles

Possible involvement of peroxynitrite in promotion of proliferative activity in the neural stem/progenitor cells after hippocampal dentate granule cell loss

Possible involvement of peroxynitrite in promotion of proliferative activity in the neural stem/progenitor cells after hippocampal dentate granule cell loss

A dual function of Bcl11b/Ctip2 in hippocampal neurogenesis

The development of the dentate gyrus is characterized by distinct phases establishing a durable stem-cell pool required for postnatal and adult neurogenesis. Here, we report that Bcl11b/Ctip2, a zinc finger transcription factor expressed in postmitotic neurons, plays a critical role during postnatal development of the dentate gyrus. Forebrain-specific ablation of Bcl11b uncovers dual phase-specific functions of Bcl11b demonstrated by feedback control of the progenitor cell compartment as well as regulation of granule cell differentiation, leading to impaired spatial learning and memory in mutants. Surprisingly, we identified Desmoplakin as a direct transcriptional target of Bcl11b. Similarly to Bcl11b, postnatal neurogenesis and granule cell differentiation are impaired in Desmoplakin mutants. Re-expression of Desmoplakin in Bcl11b mutants rescues impaired neurogenesis, suggesting Desmoplakin to be an essential downstream effector of Bcl11b in hippocampal development. Together, our data define an important novel regulatory pathway in hippocampal development, by linking transcriptional functions of Bcl11b to Desmoplakin, a molecule known to act on cell adhesion.

Viral interference with neuronal integrity: what can we learn from the Borna disease virus?

The neurotropic Borna disease virus (BDV) is unusual in that it can persistently infect neurons of the central nervous system (CNS) without causing general cell death, reflecting its favourable adaptation to the brain. The activity-dependent enhancement of neuronal network activity is however disturbed after BDV infection, possibly by its effect on the protein kinase C signalling pathway. The best model for studying BDV, which has a non-cytolytic replication strategy in primary neurons, is the rat. Infection of adult rats results in a fatal immune-mediated disease, whereas BDV establishes persistent infection of the brain in newborn rats resulting in progressive neuronal cell loss in defined regions of the CNS. Our recently developed system of BDV-infected hippocampal slice cultures has clearly shown that the onset of granule cell loss begins after the formation of the mossy fibre projection. Quantitative analysis has revealed a significant increase in synaptic density on identified remaining granule cell dendrites at 6weeks after infection, followed by a decline. Granule cells are the major target of entorhinal afferents. However, despite an almost complete loss of dentate granule cells during BDV infection, entorhinal axons persist in their correct layer, both in vivo and in slice cultures, possibly exploiting rewiring capabilities and thereby allowing new synapse formation with available targets. These morphological observations, together with electrophysiological and biochemical data, indicate that BDV is a suitable model virus for studying virus-induced morphological and functional changes of neurons and connectivity patterns.

Interleukin-1 Mediates Long-Term Hippocampal Dentate Granule Cell Loss Following Postnatal Viral Infection

Viral infections of the developing CNS can cause long-term neuropathological sequela through undefined mechanisms. Proinflammatory cytokines such as IL-1beta have gained attention in mediating neurodegeneration in corticohippocampal structures due to a variety of insults in adults, though there is less information on the developing brain. Little is known concerning the spatial-temporal pattern of IL-1beta induction in the developing hippocampus following live virus infection, and there are few studies addressing the long-term consequences of this cytokine induction. We report that infection of rats with lymphocytic choriomeningitis virus on postnatal day 4 induces IL-1beta protein in select regions of the hippocampus on 6, 15, 21, and 45 days after infection. This infection resulted in a 71% reduction of dentate granule cell neurons by the time the rats reached mid-adulthood. We further investigated the causative role of IL-1 in this dentate granule cell loss by blocking IL-1 activity using an IL-1ra-expressing adenoviral vector administered at the time of infection. Blockade of IL-1 abrogated the infection-associated neuron loss in this vivo model. Considering that IL-1 can be triggered by multiple perinatal insults, our findings suggest that early therapy with anti-inflammatory agents that block IL-1 may be effective for reducing adulthood neuropathology.

Colchicine-induced dentate granule cell loss impairs behavioral effects of acute but not chronic antidepressants

Colchicine-induced dentate granule cell loss impairs behavioral effects of acute but not chronic antidepressants

Neurogenesis in the human hippocampus and its relevance to temporal lobe epilepsies

Ample evidence points to the dentate gyrus as anatomical region for persistent neurogenesis in the adult mammalian brain. This has been confirmed in a variety of animal models under physiological as well as pathophysiological conditions. Notwithstanding, similar experiments are difficult to perform in humans. Postmortem studies demonstrated persisting neurogenesis in the elderly human brain. In addition, neural precursor cells can be isolated from surgical specimens obtained from patients with intractable temporal lobe epilepsy (TLE) and propagated or differentiated into neuronal and glial lineages. It remains a controversial issue, whether epileptic seizures have an effect on or even increase hippocampal neurogenesis in humans. Recent data support the notion that seizures induce neurogenesis in young patients, whereas the capacity of neuronal recruitment and proliferation decreases with age. Animal models of TLE further indicate that these newly generated neurons integrate into epileptogenic networks and contribute to increased seizure susceptibility. However, pathomorphological disturbances within the epileptic hippocampus, such as granule cell dispersion (GCD), may not directly result from compromised neurogenesis. Still, the majority of adult TLE patients present with significant dentate granule cell loss at an end stage of the disease, which relates to severe memory and learning disabilities. In conclusion, surgical specimens obtained from TLE patients represent an important tool to study mechanisms of stem cell recruitment, proliferation and differentiation in the human brain. In addition, increasing availability of surgical specimens opens new avenues to systematically explore disease pathomechanisms in chronic epilepsies.

Virus-Induced Injury of the Dentate Gyrus: Deconstructing the Gate in the Way of Seizures

Kappa Opioid Control of Seizures Produced by a Virus in an Animal Model Solbrig MV, Adrian R, Baratta J, Lauterborn JC, Koob GF Brain 2006;129(Pt 3):642–654 Epilepsy remains a major medical problem of unknown aetiology. Potentially, viruses can be environmental triggers for development of seizures in genetically vulnerable individuals. An estimated half of encephalitis patients experience seizures and 4% develop status epilepticus. Epilepsy vulnerability has been associated with a dynorphin promoter region polymorphism or low dynorphin expression genotype, in man. In animals, the dynorphin system in the hippocampus is known to regulate excitability. The present study was designed to test the hypothesis that reduced dynorphin expression in the dentate gyrus of hippocampus due to periadolescent virus exposure leads to epileptic responses. Encephalitis produced by the neurotropic Borna disease virus in the rat caused epileptic responses and dynorphin to disappear via dentate granule cell loss, failed neurogenesis and poor survival of new neurons. Kappa opioid (dynorphin) agonists prevented the behavioural and electroencephalographic seizures produced by convulsant compounds, and these effects were associated with an absence of dynorphin from the dentate gyrus granule cell layer and upregulation of enkephalin in CA1 interneurons, thus reproducing a neurochemical marker of epilepsy, namely low dynorphin tone. A key role for kappa opioids in anticonvulsant protection provides a framework for exploration of viral and other insults that increase seizure vulnerability and may provide insights into potential interventions for treatment of epilepsy.

Kappa opioid control of seizures produced by a virus in an animal model

Epilepsy remains a major medical problem of unknown aetiology. Potentially, viruses can be environmental triggers for development of seizures in genetically vulnerable individuals. An estimated half of encephalitis patients experience seizures and approximately 4% develop status epilepticus. Epilepsy vulnerability has been associated with a dynorphin promoter region polymorphism or low dynorphin expression genotype, in man. In animals, the dynorphin system in the hippocampus is known to regulate excitability. The present study was designed to test the hypothesis that reduced dynorphin expression in the dentate gyrus of hippocampus due to periadolescent virus exposure leads to epileptic responses. Encephalitis produced by the neurotropic Borna disease virus in the rat caused epileptic responses and dynorphin to disappear via dentate granule cell loss, failed neurogenesis and poor survival of new neurons. Kappa opioid (dynorphin) agonists prevented the behavioural and electroencephalographic seizures produced by convulsant compounds, and these effects were associated with an absence of dynorphin from the dentate gyrus granule cell layer and upregulation of enkephalin in CA1 interneurons, thus reproducing a neurochemical marker of epilepsy, namely low dynorphin tone. A key role for kappa opioids in anticonvulsant protection provides a framework for exploration of viral and other insults that increase seizure vulnerability and may provide insights into potential interventions for treatment of epilepsy.

Alterations in cyclin A, B, and D1 in mouse dentate gyrus following TMT-induced hippocampal damage.

The interactions of glia and neurons during injury and subsequent neurodegeneration are a subject of interest both in disease and chemical-induced brain injury. One such model is the prototypical hippocampal toxicant trimethyltin (TMT). An acute injection of TMT (2.0 mg/kg, i.p.) to postnatal day 21 CD-1 male mice produced neuronal necrosis and loss of dentate granule cells, astrocyte hypertrophy, and microglia activation in the hippocampus within 24 hrs. Neuronal necrosis and microglia differentiation to a phagocytic phenotype is temporally correlated with peak elevations in TNF-alpha, cyclin A2, cyclin B1 and cyclin D1 at 72 h post-TMT. TNF-alpha mRNA levels were significantly elevated in the hippocampus by 12 h and remained elevated for 72 h. mRNA levels for cyclin A2 and cyclin B1 were elevated by approximately 2-fold at 72 h. Immunohistochemistry suggested a cellular localization of cyclin A to microglia in the region of neuronal necrosis in the dentate, cyclin B in glial cells in juxtaposition to neurons in the hilus of the hippocampus and cyclin D1 to non-glial cells in the dentate. mRNA levels for cyclin D1 were elevated approximately 1.5-fold by 72 h as determined by RNase protection assay. No changes were seen in mRNA levels for cyclins E, F, G1, G2, H or I nor cyclin dependent kinases. These elevations are not associated with proliferation of microglia as determined by BrdU incorporation and Ki-67 immunohistochemistry. Upregulation of cell cycle genes was associated with cellular processes other than proliferation and may contribute to the differentiation of microglia to a phagocytic phenotype. These data suggest an integrated role for cell cycle regulation of neural cells in the manifestation of hippocampal pathophysiology.

Neonatal Viral Infection Decreases Neuronal Progenitors and Impairs Adult Neurogenesis in the Hippocampus

While adult neurogenesis has been demonstrated in the hippocampal dentate gyrus of several mammalian species, including humans, the impact of viral infections has not been well studied. To examine this question we used a model in which neonatal rats are infected with lymphocytic choriomeningitis virus (LCMV) leading to a gradual loss of dentate granule cells (DGCs), which becomes fully evident in adulthood. Stereological cell counts performed 8 months after infection revealed that the loss of mature DGCs was accompanied by an 84.2% reduction in proliferation of DGCs as measured by BrdU uptake. Moreover, there was a severe loss of Mash1-labeled neuronal progenitor cells (87 and 83% decrease in the granule cell layer and hilus, respectively). Thus, neurogenesis is impaired in this model of chronic DGC loss, perhaps due to a virus-induced impoverishment of DGC neuronal progenitors. The LCMV model could be exploited to examine pathophysiological mechanisms of neurodegeneration and to test pharmacological strategies aimed at increasing neurogenesis or rescuing multipotent progenitors.

Low levels of brain-derived neurotrophic factor and tyrosine kinase receptor B are related to loss of dentate granule cells after prolonged low-protein feeding in the rat

Protein deprivation leads to neuronal and synaptic loss in the hippocampal formation, and to behavioral changes. We suggested that these effects could result from alterations in the levels of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB). To investigate this issue, adult rats were submitted to protein deprivation for 6 months and compared with controls. The number of neurons of the dentate gyrus granular layer containing BDNF and TrkB was estimated from immunostained sections and the mRNA levels of BDNF and TrkB evaluated using in situ hybridization. After treatment, there was a loss of BDNF- and TrkB-immunoreactive cells and a reduction of the mRNA levels. Thus, it is likely that the decreased neurotrophic activity in the dentate gyrus of malnourished animals underpins neuronal degeneration and the ensuing behavioral alterations.

Injury‐induced differential gene expression in laser captured hippocampal pyramidal and dentate granule cells

Trimethyltin (TMT) is a neurotoxicant that produces a specific pattern of neuronal degeneration in the hippocampus. In mice, TMT induces a selective neuronal loss of dentate granule cells, astrocyte hypertrophy, and microglia activation. Previous studies in our laboratory demonstrated an early elevation in TNFα mRNA levels suggesting a role in initiation of the injury response. To investigate the role of TNF in this differential susceptibility of distinct neuronal populations, laser capture microdissection (LCM) was used to isolate cells in either the dentate gyrus (DG) or the CA pyramidal layer. RNA levels for TNFα, TNF receptor (TNFR) 1 and TNFR2 were measured in each distinct LCM region by real time RT–PCR. In control tissue, mRNA levels of TNFR2 and, to a lesser extent, TNFR1 were higher in cells of the DG as compared to the pyramidal cell layer. 24 h post‐TMT, the level of TNFα transcript was elevated. Consistent with the pattern of neuronal susceptibility, levels were significantly greater in the dentate region. While this differential pattern was evident at the time of neuronal necrosis, we examined differential effects at an earlier time point of 6 h. RNA from each region, as obtained by LCM, was amplified by a PCR‐based method, and hybridized to 1176 mouse cDNA arrays. Diverse categories of gene were differently express in the two regions including transcription factors (NEX‐1, LKLF), chemokines (MIP1α and β), G proteins (guanine nucleotide binding proteins) and protein kinase (PKCβ, PKCδ, KCIP1). Thus, prior to any evidence of neurodegeneration, significant alterations were detected in distinct cell regions. These results demonstrate the utility of applying these techniques to examine differential vulnerability of neurons in various models of neurodegeneration.

Viral infection of developing GABAergic neurons in a model of hippocampal disinhibition.

Mechanisms by which perinatal viral infections can disrupt hippocampal development and cause selective neuronal death may have implications for temporal lobe epilepsy and schizophrenia. Despite abnormalities of inhibitory interneurons in these diseases, the causal relationships between such neurotransmitter changes and viral infections remain unclear. This relationship was examined in a model in which rats, infected with lymphocytic choriomeningitis virus (LCMV) as neonates, manifest a gradual loss of hippocampal dentate granule cells and neuronal hyperexcitability. The current data demonstrate that GABAergic interneurons are dual immunostained for LCMV antigens prior to the loss of dentate granule cells, supporting the hypothesis that LCMV may disrupt developing inhibitory circuits causing unbalanced excitatory neurotransmission and the eventual death of dentate granule cells due to excitotoxicity.

Ethanol induces MAP2 changes in organotypic hippocampal slice cultures.

Microtubule-associated protein 2 (MAP2) and neuron-specific protein (NeuN) immunostains were used to demonstrate neurotoxic effects in mature hippocampal slice cultures exposed to ethanol (50, 100, 200 mM) for 4 weeks. At the low dose the density of MAP2 immunostaining in the dentate molecular layer was 118% of the control cultures, with no detectable changes in CA1 and CA3. At 100 mM no changes were detected, while 200 mM ethanol significantly reduced the MAP2 density in both dentate (19%) and hippocampal dendritic fields (CA3, 52%; CA1, 55%). At this dose NeuN staining showed considerable loss of CA3 pyramidal cells and moderate loss of dentate granule cells, as seen in vivo. The results indicate that brain slice cultures combined with immunostaining for cytoskeleton and neuronal markers can be used for studies of ethanol and organic solvent neurotoxicity.

Apoptosis and necrosis induced in different hippocampal neuron populations by repetitive perforant path stimulation in the rat.

Patients experiencing spontaneous seizures of temporal lobe origin often exhibit a shrunken hippocampus, which results from the loss of dentate granule cells, hilar neurons, and hippocampal pyramidal cells. Although experimental attempts to replicate the human pattern of hippocampal sclerosis in animals indicate that prolonged seizures cause prominent injury to dentate hilar neurons and hippocampal pyramidal cells, dentate granule cells of animals are generally regarded as relatively resistant to seizure-induced injury. By evaluating pathology shortly after hippocampal seizure discharges were induced electrically, we discovered that some granule cells are highly vulnerable to prolonged excitation and that they exhibit acute degenerative features distinct from those of other vulnerable cell populations. Intermittent perforant path stimulation for 24 hours induced acute degeneration of dentate granule cells, dentate hilar neurons, and hippocampal pyramidal cells. However, stimulation for 8 hours, which was insufficient to injure hilar neurons and hippocampal pyramidal cells, was nonetheless sufficient to induce bilateral granule cell degeneration. Degenerating granule cells were consistently more numerous in the infrapyramidal than the suprapyramidal blade, and were consistently more numerous in the rostral than caudal dentate gyrus. Depending on the nature of the insult, acutely degenerating neurons exhibit distinct morphological features that are classifiable as either apoptosis or necrosis, although the degree of possible overlap is unknown. Light and electron microscopic analysis of the acute pathology caused by prolonged afferent stimulation revealed that degenerating hilar neurons and pyramidal cells exhibited the morphological features of necrosis, which is characterized in part by early cytoplasmic vacuolization before nuclear changes occur. However, acutely degenerating granule cells exhibited the clearly distinct morphological features of apoptosis, which include an early coalescence of nuclear chromatin into multiple nuclear bodies, compaction of the cytoplasm, cell shrinkage, and budding-off of 'apoptotic bodies' that are engulfed by glia. Whereas pyramidal cell debris persisted for months, granule cell debris disappeared rapidly. This observation may explain why significant granule cell vulnerability has not been described previously. These data document for the first time that dentate granule cells are among the cell types most vulnerable to seizure-induced injury, and demonstrate that whereas hilar neurons and pyramidal cells undergo a typically necrotic degenerative process, granule cells simultaneously exhibit morphological features that more closely resemble the degenerative process of apoptosis. This finding implies that the type of cell death induced by excessive excitation may be determined postsynaptically by the way in which different target cells 'interpret' an excitatory insult. This experimental model may be useful for identifying the biochemical mechanisms that initiate and mediate neuronal apoptosis and necrosis, and for developing strategies to prevent or induce these presumably distinct forms of neuronal death.

Regulation of prodynorphin gene expression in the hippocampus by glucocorticoids

The regulation of prodynorphin gene expression by glucocorticoids in the hippocampus was examined in rats that were adrenalectomized (ADX) either 7, 30, 60 and 90 days prior to sacrifice. Peptide levels in the hippocampus of ADX rats were determined by radioimmunoassay and immunocytochemistry. Prodynorphin (PDYN) mRNA was measured by Northern blot analysis and in situ hybridization. A time-dependent decrease in dynorphin A(1–8) (DYN) levels in the hippocampus (18% at 7 days; 44% at 30 days; 58% at 60 days) of ADX rats was found, which was accompanied by a comparable decrease in the abundance of PDYN mRNA. An in situ hybridization analysis revealed that both the number of positively hybridized cells and the number of silver grains per cell were decreased in the dentate gyrus after ADX. The administration of dexamethasone after surgery reversed the peptide and mRNA attenuation induced by ADX. ADX had no effect on the expression of proenkephalin mRNA or [Met 5]-enkephalin immunoreactivity in the hippocampus. Examination of thionin-counterstained tissue showed that the dentate granule cell layer was intact. The decrement of DYN expression in this system is proposed to have resulted from the removal of glucocorticoid input and not dentate granule cell loss. This study provides the strong evidence for a differential susceptibility of these two opioid peptides in the hippocampus to the removal of glucocorticoids. In addition, these data provide support for a potentially selective, glucocorticoid-permissive component in PDYN gene expression.

Induction of paroxysmal discharges in the dentate gyrus: frequency dependence and relationship to afterdischarge production.

1. Electrical-stimulus trains activated hippocampal circuits in urethan-anesthetized rats. Responses were monitored with recordings of extracellular potentials and with measurements of the extracellular potassium ([K+]o). Stimulating electrodes were placed in the CA3 region contralateral to the recording electrode (cCA3) and in the ipsilateral angular bundle (AB) while recording in the CA1 pyramidal-cell layer or the granule-cell layer of the dentate gyrus. Patterns of maximal activation were identified. 2. In the CA1 region, maximal activation was indicated by the presence of 10- to 15-mV population spikes, a smooth rise in [K+]o of 5-6 mM above base-line levels of 3 mM, and a negative shift of the sustained DC potential of 2-4 mV. The dentate gyrus was considered to be maximally activated when bursts of large-amplitude (20-40 mV) population spikes were present. These population spikes were associated with a secondary rise in [K+]o to 6-8 mM above base line and an abrupt negative shift of the DC potential of 5-8 mV. 3. Maximal activation depended on the stimulus intensity, frequency, and duration. Trains of 10-Hz stimuli were used to determine the lowest stimulus intensity needed to elicit complete activation in CA1 and in the dentate gyrus. At this intensity, afterdischarges were not produced, and these responses could be elicited repeatedly. 4. By the use of this threshold stimulus intensity, cCA3 stimulation produced a rapid and progressive augmentation of CA1 responses until maximal activation was reached. In comparison, stimulation of the AB could produce the same end result, but the appearance of CA1 population spikes was delayed. Stimulation of the AB produced a steady increase in the evoked granule-cell population spike until the appearance of the paroxysmal large-amplitude population spikes. In contrast, cCA3 stimulation produced two positive evoked responses in the dentate gyrus before the paroxysms of population spikes began. 5. The frequency dependence of the responses was determined by giving stimulus trains ranging from 2 to 100 Hz. Stimulation of cCA3 produced population spikes in CA1 up to 100 Hz that were all associated with the same peak rise in [K+]o. AB stimulation only produced CA1 responses with stimulation frequencies between 15 and 25 Hz. The paroxysmal dentate population spikes were generated by stimulus frequencies between 15 and 30 Hz with both AB and cCA3 stimulation. 6. Unilateral colchicine injections caused a loss of dentate granule cells and a loss of maximal dentate activation on the side of the injection.(ABSTRACT TRUNCATED AT 400 WORDS)

The time-course of trimethyltin-induced fiber and terminal degeneration in hippocampus

Trimethyltin (TMT) produces prominent neuron death in the hippocampus. The time-course of TMT-induced damage was studied using reduced-silver procedures for impregnation of degenerating axons and their terminals, and a modified Timm's stain procedure for visualization of hippocampal transitional metals. Standard cell body stains were also used. Fifty-four, adult, Long-Evans rats were gavaged with 6.0 mg TMT/kg b.wt. and 10 rats were gavaged with distilled water as controls. Five TMT-gavaged rats and one saline-gavaged rat were sacrificed on either postgavage day 1, 3, 6, 9, 14, 19, 30, 45, 70 or 99. Histological examination revealed a band of degenerating terminals in the stratum lucidum, below the hippocampal subfields CA3a,b pyramidal cells, by postgavage day 3. This preceded dentate gyrus granule cell loss supplying the mossy fiber input to the stratum lucidum by several days. Hippocampal pyramidal cell necrosis continued through the examination period while dentate granule cell loss subsided between postgavage days 9 and 14. Fiber and terminal degeneration was more extensive in the dorsal hippocampus than in the ventral hippocampus, although Timm's-stained sections revealed “bleaching” of stainable metal in the mossy fiber pathway of the ventral hippocampus. These data suggest that loss of ventral dentate granule cells might reduce TMT-induced necrosis of pyramidal cells in the ventral (temporal) part of the Ammon's horn, possibly by preventing the spread of seizure activity in this region of the hippocampus. Additionally, although previous studies have reported the toxic effects of TMT to last approximately 60 days, the results of the present study indicate that TMT-induced degeneration continues for more than 3 months. Reduced-silver stains, such as the Fink-Heimer procedure, appear to be more sensitive indicators of enduring neuropathology than more traditional cell stains.

Cochicine-induced granule cell loss in rat hippocampus: Selective behavioral and histological alterations

Bilateral injection of 3.5 μg of colchicine into two levels of the dentate gyrus produced a selective loss of dentate granule cells and persistent behavioral effects in male Fischer rats. Histological analysis confirmed that this dosage of colchicine resulted in the selective loss of most granule cells in both superior and inferior blades of the dentate gyrus near the injection sites, while sparing pyramidal cells in CA 1, CA 2, CA 3 and CA 4, and GABAergic interneurons throughout the hippocampus, Rats injected with colchicine were significantly more active than cerebrospinal fluid-injected controls 2, 7, 14, 21 and 28 days after treatment. Behavioral reactivity, assessed by the magnitude of the acoustic startle response and the latency to respond in a hot-plate test, was not affected at any of these time points. Retention of a step-through passive avoidance task was impaired in the colchicine group one month after surgery. Their stepthrough latencies were significantly shorter than control latencies, and they exhibited more partial entries during the retention test. Acquisition and performance in a radial-arm maze, measured up to 3 months after surgery, were also impaired by colchicine. Animals injected with colchicine required more trials to acquire the task and were less accurate in the task even after their performance had stabilized. These data suggest that the hippocampus modulates motor behavior and cognitive function. The results of these experiments also support the use of colchicine as a means of defining the functional and anatomical consequences following selective destruction of the granule cell population of the dentate gyrus.