Specifically, layer V pyramidal neurons from stargazer mice are hyperexcitable, and exhibit spontaneous giant depolarizing EPSPs, a reduction in VX-770 concentration the postburst afterhyperpolarization, and an enhancement in the hyperpolarization-activated cation current, or Ih ( Noebels et al., 1990 and Di Pasquale et al., 1997). Interestingly, stargazer/γ-3/γ-4 triple KO mice, despite not surviving past birth, do not exhibit any defect in AMPAR-mediated transmission in late embryonic neocortical neurons ( Menuz et al., 2009). Subsequent work on TARP mutants focused on neurons in the thalamus, in particular the activity of thalamic nucleus reticularis (nRT)

neurons and thalamocortical relay neurons (TRNs), which have pivotal roles to play in the generation of absence seizures (Huguenard and McCormick, 2007, Beenhakker and Huguenard, 2009 and Chetkovich, 2009). Menuz and coworkers found that glutamatergic synapses onto inhibitory

nRT neurons, but not onto excitatory TRNs, were disrupted in stargazer mice. These data suggest that disinhibition in the thalamus may contribute to seizure activity, characteristic of the stargazer mouse ( Menuz and Nicoll, 2008). In addition, CNQX and the related quinoxaline-derived compound DNQX, but not NBQX, selectively depolarize nRT neurons, but not TRNs ( Lee et al., 2010), pointing to possible cell-type-specific differences in TARP expression or function within GSK 3 inhibitor the thalamus. Finally, TARP γ-4 has also been shown to have a role to play in the generation of SWDs and absence seizures when crossed with hypomorphic stargazer alleles such as waggler and stargazer3J ( Letts et al., 2005). Future work will be required in order to dissect the functional roles

of various TARP family members in regulating glutamatergic transmission, and ultimately, the balance of excitation aminophylline and inhibition between specific cell types within corticothalamic networks. Defects in glutamatergic synaptic transmission have been implicated in the pathogenesis of numerous neurodegenerative and psychiatric diseases. Emerging human genetic evidence suggests that TARPs may play a role in the etiology of disorders as diverse as epilepsy, schizophrenia, and neuropathic pain. Homozygosity analysis of a consanguineous family exhibiting a high frequency of epilepsy, schizophrenia, and/or hearing loss revealed a link to a region of chromosome 22 that includes the human stargazin gene (CACNG2) (Knight et al., 2008). The human γ-3 gene (CACNG3) on chromosome 16 has been implicated as a susceptibility locus in a subpopulation of patients suffering from childhood absence epilepsy (CAE) (Everett et al., 2007), whereas another study of consanguineous families showed that CACNG2 is not linked with CAE (Abouda et al., 2010). In a genetic study of families with a high incidence of schizophrenia, stargazin was linked to susceptibility in a subpopulation of patients (Liu et al., 2008).