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Limbic but not non-limbic kindling impairs conditioned fear and promotes plasticity of NPY and its Y2 receptor

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Abstract

Epileptic seizures negatively affect cognition. However, the mechanisms that contribute to cognitive impairments after seizures are largely unknown. Here, we examined the effects of long-term kindling (i.e., 99 stimulations) of limbic (basolateral amygdala, dorsal hippocampus) and non-limbic (caudate nucleus) brain sites on conditioned fear and hippocampal plasticity. We first showed that kindling had no effect on acquisition of a hippocampal-dependent trace fear-conditioning task but limbic kindling impaired the retrieval of these fear memories. To determine the relationship between memory and hippocampal neuronal activity, we examined the expression of Fos protein 90 min after memory retrieval (i.e., 4 days after the last kindling stimulation). We found that limbic kindling, but not non-limbic kindling, decreased Fos expression in the granule cell layer, hilus, CA3 pyramidal cell layer, and CA1 pyramidal cell layer. Next, to investigate a mechanism that could contribute to dampen hippocampal neuronal activity in limbic-kindled rats, we focused on the endogenous anticonvulsant neuropeptide Y (NPY), which is expressed in a subset of GABAergic interneurons and can prevent glutamate release through interactions with its Y2 receptor. We found that limbic kindling significantly decreased the number of NPY-immunoreactive cells in several hippocampal subfields despite minimal staining of the neurodegenerative marker Fluoro-Jade B. However, we also noted that limbic kindling enhanced NPY immunoreactivity throughout the mossy fiber pathway. In these same regions, we observed limbic kindling-induced de novo expression of the NPY Y2 receptor. These novel findings demonstrate the site-specific effects of kindling on cognition and NPY plasticity, and they provide evidence that altered hippocampal NPY after limbic seizures coincides with dampened neural activity and cognitive impairments.

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Acknowledgments

This work was supported by a grant from the Natural Sciences and Engineering Research Council (NSERC) to LEK. LEK holds a CIHR-Canada Research Chair in Behavioral Neuroscience. JJB is supported by an NSERC postgraduate scholarship.

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Authors and Affiliations

  1. Department of Psychology, University of Saskatchewan, Saskatoon, SK, S7N 5A5, Canada

    J. J. Botterill, A. J. Guskjolen & W. N. Marks

  2. College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, S7N 5A5, Canada

    H. J. Caruncho

  3. Department of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada

    L. E. Kalynchuk

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  1. J. J. Botterill
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  2. A. J. Guskjolen
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  3. W. N. Marks
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  5. L. E. Kalynchuk
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Correspondence to L. E. Kalynchuk.

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Botterill, J.J., Guskjolen, A.J., Marks, W.N. et al. Limbic but not non-limbic kindling impairs conditioned fear and promotes plasticity of NPY and its Y2 receptor. Brain Struct Funct 220, 3641–3655 (2015). https://doi.org/10.1007/s00429-014-0880-z

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