title: Rescue of synaptic plasticity and spatial learning deficits in the hippocampus of Homer1 knockout mice by recombinant Adeno-associated viral gene delivery of Homer1c.
abstract: Homer1 belongs to a family of scaffolding proteins that interact with various post-synaptic density proteins including group I metabotropic glutamate receptors (mGluR1/5). Previous research in our laboratory implicates the Homer1c isoform in spatial learning. Homer1 knockout mice (H1-KO) display cognitive impairments, but their synaptic plasticity properties have not been described. Here, we investigated the role of Homer1 in long-term potentiation (LTP) in the hippocampal CA1 region of H1-KO mice in vitro. We found that late-phase LTP elicited by high frequency stimulation (HFS) was impaired, and that the induction and maintenance of theta burst stimulation (TBS) LTP were reduced in H1-KO. To test the hypothesis that Homer1c was sufficient to rescue these LTP deficits, we delivered Homer1c to the hippocampus of H1-KO using recombinant adeno-associated virus (rAAV). We found that rAAV-Homer1c rescued HFS and TBS-LTP in H1-KO animals. Next, we tested whether the LTP rescue by Homer1c was occurring via mGluR1/5. A selective mGluR5 antagonist, but not an mGluR1 antagonist, blocked the Homer1c-induced recovery of late-LTP, suggesting that Homer1c mediates functional effects on plasticity via mGluR5. To investigate the role of Homer1c in spatial learning, we injected rAAV-Homer1c to the hippocampus of H1-KO. We found that rAAV-Homer1c significantly improved H1-KO performance in the Radial Arm Water Maze. These results point to a significant role for Homer1c in synaptic plasticity and learning.
authors.affiliation: Department of Neurology, University of Wisconsin-Madison, Medical Sciences Center, 1300 University Ave., Room 73 Bardeen, Madison, WI 53706, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Gerstein
authors.forename: Kenneth
authors.initials: K
authors.lastname: O'Riordan
authors.forename: Sue
authors.initials: S
authors.lastname: Osting
authors.forename: Martin
authors.initials: M
authors.lastname: Schwarz
authors.forename: Corinna
authors.initials: C
authors.lastname: Burger
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001565:Benzoates / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D000072233:Homer Scaffolding Proteins; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D012919:Social Behavior; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D001565:Benzoates; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; C079694:alpha-methyl-4-carboxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; D005998:Glycine