(2008). Both γ-7 and γ-5 enhance the mean channel conductance and have a modest effect on the rectification

of Glu4 homomers. In striking contrast to Kato et al. (2008), γ-5 SB203580 was found to preferentially modulate the mean channel conductance of AMPARs composed of “long-form” subunits, which are predominantly GluA2 lacking and calcium permeable (Soto et al., 2009) (Table 1). Further study will be required to reconcile these contradictory findings. Nevertheless, the unique characteristics of type II TARPs add a degree of functional diversity, and possibly bidirectional control, to AMPAR trafficking and gating. TARPs exhibit widespread and extensively overlapping expression patterns throughout the brain as assessed by in situ

hybridization. Type I and II TARPs are found in both neurons and glia and display complex, cell-type-specific expression that varies over the course of development (Tomita et al., 2003, Fukaya et al., 2005 and Lein et al., 2007). Given their apparent functional redundancy, why are there Vorinostat chemical structure so many TARP family members? Why do some cell types appear to only express one TARP subtype while another expresses a multitude? A great deal can be learned about the subtype-specific role of TARPs in brain function by examining their differential expression patterns and complex effects on AMPAR trafficking and gating following their genetic deletion. A useful way of unpacking these questions is to consider TARP subtype-specific effects in well-characterized cell types in the hippocampus, cerebellum, neocortex, and thalamus (Table 2). Because the expression of synaptic plasticity at Schaffer colateral-CA1 pyramidal neuron synapses depends

on the activity-dependent regulation of postsynaptic AMPARs (Malenka and Bear, 2004 and Kerchner and Nicoll, 2008), a compelling issue since the discovery of TARPs has been discerning their role in modulating AMPAR trafficking and plasticity in these neurons. CA1 pyramidal neurons are known to express multiple TARP family members, including stargazin, γ-3, γ-4, γ7, and γ-8. However, a striking and unique feature of the hippocampus is the selective enrichment of STK38 γ-8 (Tomita et al., 2003, Fukaya et al., 2005 and Lein et al., 2007). The generation of the γ-8 knockout (KO) mouse revealed that AMPAR expression and distribution are selectively diminished in the hippocampus, as evidenced by the dramatic reduction in hippocampal GluA subunit protein expression without a corresponding change in amounts of mRNA. At the subcellular level, immunogold electron microscopy showed that both synaptic and extrasynaptic AMPARs are severely diminished. Interestingly, CA1 pyramidal neurons from γ-8 KO mice exhibit relatively modest reductions in field EPSC (fEPSC) slope, AMPA/NMDA ratio, and mEPSC amplitude, but do exhibit the near-complete loss of extrasynaptic AMPARs.