Norbin Is an Endogenous Regulator of Metabotropic Glutamate Receptor 5 Signaling

Norbin Knockout Metabotropic glutamate receptors (mGluRs) are critical neurotransmitter sensors implicated in central neuronal functions like learning and memory and in diseases of the nervous system. Wang et al. (p. 1554) searched for proteins that interact with mGluR5a and identified a previously unrecognized component of the receptor signaling complex. The protein Norbin directly interacted with the receptor. Loss of Norbin in mice or cultured cells showed that it is necessary for the accumulation of mGluR5a in the cell membrane, for normal modulation of synaptic plasticity, and for some behavioral responses. The protein Norbin regulates the accumulation of a neurotransmitter receptor in mouse brain cell membranes. Metabotropic glutamate receptor 5 (mGluR5) is highly expressed in the mammalian central nervous system (CNS). It is involved in multiple physiological functions and is a target for treatment of various CNS disorders, including schizophrenia. We report that Norbin, a neuron-specific protein, physically interacts with mGluR5 in vivo, increases the cell surface localization of the receptor, and positively regulates mGluR5 signaling. Genetic deletion of Norbin attenuates mGluR5-dependent stable changes in synaptic function measured as long-term depression or long-term potentiation of synaptic transmission in the hippocampus. As with mGluR5 knockout mice or mice treated with mGluR5-selective antagonists, Norbin knockout mice showed a behavioral phenotype associated with a rodent model of schizophrenia, as indexed by alterations both in sensorimotor gating and psychotomimetic-induced locomotor activity.

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