Hippocampal Homer1b/c is necessary for contextual fear conditioning and group I metabotropic glutamate receptor mediated long-term depression.

Coiled-coil forms of Homer1, including Homer1b and c (Homer1b/c) have been shown to play a role in hippocampal learning and memory and synaptic plasticity. We have previously found that overexpression of hippocampal Homer1c is sufficient to rescue learning and memory ability in aged learning impaired rats and in Homer1 knockout (KO) mice, and to rescue group I metabotropic glutamate receptor (mGluR1/5) mediated long-term potentiation in KO mice. Here, to determine if Homer1b/c is necessary for successful learning and memory we have utilized a rAAV5 vector expressing a Homer1b/c-targeting short hairpin RNA to knock down the expression of hippocampal Homer1b/c in adult 4-6-month old male Sprague Dawley rats. We have found that reduced hippocampal Homer1b/c expression elicits significant learning deficits in contextual fear conditioning, but not in the Morris water maze or novel object recognition tasks. Furthermore, we demonstrate that reduced hippocampal Homer1b/c is sufficient to completely block mGluR1/5 mediated long-term depression in the Schaffer collateral pathway. These results support a significant role for Homer1b/c in learning and synaptic plasticity; however, the exact role of each of these two protein isoforms in learning and memory remains elusive.