This Week in The Journal

Teresa Esch

Striatal Kainate Receptors Stimulate Cannabinoid Signaling

John J. Marshall, Jian Xu, and Anis Contractor

Kainate receptors (KARs) are ionotropic glutamate receptors expressed at both presynaptic and postsynaptic sites throughout the nervous system. KARs have slower kinetics than AMPA receptors and they are thought to contribute minimally to postsynaptic currents in most neurons. Instead, their prolonged activation likely facilitates temporal summation and synaptic integration. In addition, KARs can exert effects without passing current, by initiating non-canonical, metabotropic signaling through G-proteins. Metabotropic signaling via postsynaptic KARs is thought to inhibit the slow afterhyperpolarization, and thus to enhance spiking of hippocampal neurons. In contrast, metabotropic signaling mediated by presynaptic KARs in the hippocampus can inhibit neurotransmitter release (Valbuena and Lerma, 2016 Neuron 92:316). Marshall et al. now provide evidence that activation of postsynaptic KARs in striatal projection neurons (SPNs) also reduces glutamate release from presynaptic afferents by stimulating release of endocannabinoids.

Application of kainate (shaded area) reduces the amplitude of EPSCs evoked in D1-SPNs by stimulation of corticostriatal afferents (blue). This effect was blocked by an antagonist of CB1Rs (red). See Marshall et al. for details.

The authors stimulated corticostriatal afferents in brain slices and recorded EPSCs in SPNs that expressed D1-dopamine receptors (D1-SPNs). Application of kainate at concentrations too low to evoke substantial inward currents reduced the amplitude and increased the paired-pulse ratio of corticostriatal EPSCs in D1-SPNs, suggesting it decreased presynaptic glutamate release. This effect was absent when the KAR subunit GluK2 was knocked out selectively in D1-SPNs. Kainate-induced suppression of EPSCs was also attenuated by blocking striatal endocannabinoid receptors (CB1Rs) or G-protein function, by chelating calcium, and by inhibiting hydrolysis of diacylglycerol, which produces the endocannabinoid 2-AG. Notably, driving spike trains in corticostriatal afferents also suppressed EPSCs in D1-SPNs, and this was prevented by a CB1R antagonist or knocking out GluK2. Kainate did not suppress corticostriatal EPSCs in D2-SPNs.

These results suggest that KAR activation in D1-SPNs reduces presynaptic glutamate release from cortical afferents by activating G-protein-dependent signaling and calcium-dependent production of 2-AG, which activates presynaptic CB1Rs. Although activation of the metabotropic glutamate receptor mGluR5 suppresses corticostriatal EPSCs in D1-SPNs through a similar signaling pathway, an mGluR5 antagonist did not affect suppression of corticostriatal EPSCs resulting from either kainate treatment or afferent stimulation, suggesting the two pathways are activated under different conditions. The function of KAR-induced suppression of corticostriatal EPSCs in D1-SPNs remains unclear, but it might facilitate task switching by reducing drive from active cortical neurons.

Vault Protein Contributes to Ocular Dominance Plasticity

Jacque P.K. Ip, Ikue Nagakura, Jeremy Petravicz, Keji Li, Erik A.C. Wiemer, et al.

(see pages 3890–3900)

Vaults are large, enigmatic, ribonucleoprotein particles found in nearly all cell types across the animal kingdom. Up to 96 molecules of major vault protein (MVP) come together to form the outer shell of these hollow capsules, which are more than twice the size of ribosomes. Vaults are present predominantly in the cytoplasm, often associated with microtubules, but they can also enter the nucleus. Based on their structure and location, vaults have been hypothesized to play roles in intracellular transport, including shuttling signaling molecules between the cytoplasm and nucleus. Consistent with this, MVP interacts with MAPK and ERK kinases and influences nuclear import of the phosphatase PTEN and the transcription factor STAT1 (Berger et al., 2008 Cell Mol Life Sci 66:43). New evidence suggests that vaults also participate in some forms of plasticity in the mammalian CNS.

MVP is located on chromosome 16p11.2, in a region that is deleted in some people with autism spectrum disorders and other neurodevelopmental disorders. To assess its role in neural plasticity, Ip, Nagakura, et al. studied the effects of monocular deprivation in mice lacking one copy of MVP. In wild-type mice, suturing one eyelid closed for 7 d altered the responsiveness of primary visual cortical (V1) neurons to input from each eye: responses to the formerly closed eye decreased and responses to the other eye increased. Although monocular deprivation decreased responses to the deprived eye in MVP^+/− mice, responses to the open eye did not change. Furthermore, whereas the amplitude of miniature EPSCs (mEPSCs) in V1 pyramidal neurons increased after monocular deprivation in control mice, mEPSC amplitude and frequency decreased in MVP^+/− mice. Postnatal knockdown of MVP in V1 also reduced plasticity of open-eye responses after monocular deprivation, and this effect was partially rescued by simultaneously knocking down STAT1.

These results indicate that MVP contributes to a major component of ocular dominance plasticity, namely the homeostatic increase in neuronal responsiveness to inputs from the non-deprived eye, which is thought to compensate for loss of synaptic drive from the closed eye. Whether MVP is involved in other forms of homeostatic plasticity and how it contributes to this plasticity at the molecular level should be investigated in future studies.