Discovery and Characterization of Novel CNS-Penetrant GPR55 Agonists.

From our NETSseq-derived human brain transcriptomics data, we identified GPR55 as a potential molecular target for the treatment of motor symptoms in patients with Parkinson's disease. From a high-throughput screen, we identified and optimized agonists with nanomolar potency against both human and rat GPR55. We discovered compounds with either strong or limited β-arrestin signaling and receptor desensitization, indicating biased signaling.

Discovery of , a Novel Brain-Penetrant α6-Containing Nicotinic Receptor Antagonist for the Modulation of Motor Dysfunction.

Nicotinic acetylcholine receptor (nAChR) α6 subunit RNA expression is relatively restricted to midbrain regions and is located presynaptically on dopaminergic neurons projecting to the striatum. This subunit modulates dopamine neurotransmission and may have therapeutic potential in movement disorders. We aimed to develop potent and selective α6-containing nAChR antagonists to explore modulation of dopamine release and regulation of motor function in vivo.

Contribution of aberrant GluK2-containing kainate receptors to chronic seizures in temporal lobe epilepsy.

Kainate is a potent neurotoxin known to induce acute seizures. However, whether kainate receptors (KARs) play any role in the pathophysiology of temporal lobe epilepsy (TLE) is not known. In TLE, recurrent mossy fiber (rMF) axons form abnormal excitatory synapses onto other dentate granule cells that operate via KARs.

Ephrin-B3 regulates glutamate receptor signaling at hippocampal synapses.

B-ephrin-EphB receptor signaling modulates NMDA receptors by inducing tyrosine phosphorylation of NR2 subunits. Ephrins and EphB RTKs are localized to postsynaptic compartments in the CA1, and therefore potentially interact in a non-canonical cis- configuration. However, it is not known whether cis- configured receptor-ligand signaling is utilized by this class of RTKs, and whether this might influence excitatory synapses.

AMPA receptor desensitization mutation results in severe developmental phenotypes and early postnatal lethality.

AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate) recep-tors desensitize rapidly and completely in the continued presence of their endogenous ligand glutamate; however, it is not clear what role AMPA receptor desensitization plays in the brain. We generated a knock-in mouse in which a single amino acid residue, which controls desensitization, was mutated in the GluA2 (GluR2) receptor subunit (GluA2(L483Y)). This mutation was homozygous lethal.

Bi-directional alterations of LTP after acute homocysteine exposure.

Homocysteine (HCY) is a known risk factor for neuronal diseases. We here report that HCY (10-1000 microM) interfered bi-directionally with long-term potentiation (LTP) in hippocampal slices, causing an impairment at concentrations <100 microM, and enhancement > or =500 microM. By comparison, NMDA unidirectionally reduced LTP, whereas l-cysteine led to facilitated LTP.

Enhanced hippocampal long-term potentiation in rats after chronic exposure to homocysteine.

Homocysteine (HCY) is a sulphur-containing amino acid, which has been linked to neurodegenerative diseases such as Alzheimer's disease, and is widely reported to enhance vulnerability of neurons to oxidative, excitotoxic and apoptotic injury via perturbed calcium homeostasis, activation of N-methyl-D-aspartate (NMDA) and metabotropic glutamate (mGlu) receptors. The present study was undertaken to investigate the effects of HCY on long-term potentiation (LTP) and synaptic transmission after chronic 4-week systemic exposure to HCY in adult rats, and possible longer-term effects of HCY 4 weeks after exposure had ended. Contrary to expectation, LTP was enhanced, not retarded after chronic HCY exposure relative to controls.

Presynaptic group I metabotropic glutamate receptors modulate synaptic transmission in the rat superior colliculus via 4-AP sensitive K(+) channels.

1. Group I metabotropic glutamate receptors (mGluRs) are thought to be important modulators of neuronal function in the superior colliculus (SC). Here, we investigated the pharmacology and signalling mechanisms underlying group I mGluR-mediated inhibition of neuronal excitability and synaptic transmission in the rat SC slice.