Human GRIA4 blocking peptide

Fast excitatory transmission in the mammalian central nervous system is mediated by AMPA-type glutamate receptors. The tetrameric AMPA receptor complexes are composed of four subunits, GluR1-4. The GluR4 subunit is highly expressed in the cerebellum and the early postnatal hippocampus and is thought to be involved in synaptic plasticity and the development of functional neural circuitry through the recruitment of other AMPA receptor subunits. Previously, we reported an association of the human GluR4 gene (GRIA4) with schizophrenia. To examine the role of the GluR4 subunit in the higher brain function, we generated GluR4 knockout mice and conducted electrophysiological and behavioural analyses. The mutant mice showed normal long-term potentiation (LTP) in the CA1 region of the hippocampus. The GluR4 knockout mice showed mildly improved spatial working memory in the T-maze test. Although the retention of spatial reference memory was intact in the mutant mice, the acquisition of spatial reference memory was impaired in the Barnes circular maze test. The GluR4 knockout mice showed impaired prepulse inhibition. These results suggest the involvement of the GluR4 subunit in cognitive function.

C3H/HeJ mice have been reported to have relatively early onset of spike-wave discharges (SWD), and a defective AMPA receptor subunit Gria4 as the genetic cause. We investigated the time course of SWD development through serial EEG recordings in C3H/HeJ mice to better characterize this model. We found that at immature postnatal ages of 5-15 days, rare SWD-like events were observed at an average rate of 3 per hour, and with relatively broad spikes, irregular rhythm, slow frequency (5-6 Hz), and short duration (mean 1.75 s). This was followed by a transitional period of increasing SWD incidence, which then stabilized in mature animals at age 26-62 days, with SWD at an average rate of 45 per hour, narrower spike morphology, regular rhythm, higher frequency (7-8 Hz), and longer duration (mean 3.40 s). This sequence of maturational changes in SWD development suggests that effects of early intervention could be tested in C3H/HeJ mice over the course of a few weeks, rather than a few months as in rats, greatly facilitating future research on anti-epileptogenesis. (C) 2009 Published by Elsevier B.V.