Abstract

Cerebellar stroke-induced cognitive and affective symptoms (CCAS) have been observed in patients with infarcts localized to the posterior regions of the cerebellum. Our lab has developed a mouse model of cerebellar stroke in which mice with posterior infarcts display hippocampal-dependent memory deficits. Synaptic plasticity in the hippocampal area CA1 is essential for episodic memory consolidation. There is evidence of functional connectivity of cerebellum with contralateral hippocampus. Therefore, we hypothesize that changes in after cerebellar stroke are the result of synaptic plasticity impairments within the hippocampus. We used a photothrombotic model to induce stroke in the posterior cerebellar hemispheres. Seven days after stroke, we performed extracellular recordings of field excitatory postsynaptic potentials (fEPSP) within the CA1 region of acute brain slices. In shams, theta-burst stimulation (TBS) of Schaffer collateral inputs produced long-term potentiation (LTP). TBS failed to evoke an increase in fEPSP slope in contralateral hippocampus of mice at 7 days post-injury. These data provide strong evidence demonstrating that injury to the cerebellum can produce changes in synaptic function within the hippocampus. The lack of LTP impairment in ipsilateral hippocampus after cerebellar stroke suggests that the observed plasticity deficits are activity dependent. We also observed reduced NMDA receptor, Fos and Arc expression. Brain-derived neurotrophic factor (BDNF) signaling through TrkB receptors is required for LTP and memory formation. We tested whether enhancement of TrkB signaling with the agonist 7, 8 dihydroflavone (DHF) could improve hippocampal plasticity. We observed a full restoration of hippocampal LTP in slices from cerebellar stroke mice that were incubated with DHF (250 nM) prior to TBS. We provide strong evidence for hippocampal dysfunction following cerebellar stroke. Our data have implications for benefit of strategies to enhance neurotrophic signaling not only at the site of injury, but in non-injured regions as well.

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