An Emerging Role for TARPs in Neuropsychiatric Disorders

The discovery of glutamate as the principal excitatory neurotransmitter in brain was followed by the identification and molecular cloning of the ionotropic glutamate receptor family, which comprises NMDA, AMPA, and kainate receptors. The AMPA receptor subfamily mediates fast synaptic neurotransmission important to diverse sensory, behavioral, and cognitive processes, including learning and memory. However, excessive AMPA receptor activity and subsequent excitotoxicity underlie central nervous system disorders ranging from stroke to epilepsy. It was hypothesized that the development of AMPA receptor antagonists to dampen aberrant neurotransmission would provide treatments for neurological illnesses. However, clinical trials have shown side effects for these antagonists and suggested a need for greater selectivity.

A seminal finding in AMPA receptor biology and neurotransmission was the discovery of stargazin, the protein mutated in stargazer mice, which show absence epilepsy and cerebellar ataxia. Cell biological and physiological studies showed that stargazin is an AMPA receptor auxiliary subunit and controls receptor trafficking, gating, and pharmacology. Subsequent studies have identified a family of related transmembrane AMPA receptor regulator proteins (TARPs). TARPs comprise γ-2 (stargazin), -3, -4, -5, -7, and -8 subunits, which are discretely distributed in specific neuronal and glial populations throughout the brain. Studies involving γ-8 knockout mice, which exhibit deficiencies in hippocampal neurotransmission, underscore the importance of TARPs both in region-specific control of AMPA receptor signaling, and in neurological disease—hippocampal excitotoxicity elicited by the AMPA receptor partial agonist, kainate, is abrogated in γ-8 knockout mice (Tomita et al, 2007).

Neuropsychiatric conditions such as schizophrenia, depression, and bipolar disorder are severe, multifactorial brain illnesses of mood, cognition, and behavior whose etiologies remain uncertain. Molecular analyses have found abnormal expression for key components of glutamatergic neurotransmission, including TARPs. Increased and decreased stargazin mRNA expression has been documented in post-mortem schizophrenic and major depressive disorder brains, respectively (Beneyto and Meador-Woodruff, 2006). Silberberg et al (2008) found certain CACNG2 (the gene that encodes stargazin) allelic polymorphisms are associated with improved response to lithium, the classical treatment for bipolar disorder. Furthermore, chronic treatment with the antidepressants desipramine and paroxetine increased AMPA receptor association with stargazin in rat hippocampus (Martinez-Turrillas et al, 2007). Patients with bipolar disorder or schizophrenia have exhibited decreased CACNG2 DNA copy number (Wilson et al, 2006). Yet, increased stargazin mRNA expression has been found in the dorsolateral prefrontal cortex of brains from bipolar disorder patients suggesting a potential regio-specific action for stargazin in this disorder (Silberberg et al, 2008). Furthermore, the PDE 11A knockout mouse, which shows multiple psychiatric illness-related phenotypes, possessed decreased hippocampal expression of both γ-2 and -8 proteins (Kelly et al, 2010).

Recent research into neuropsychiatric illnesses has shown an emerging pathological role for TARPs. As TARPs are differentially localized in neuron pathways, targeting individual isoforms may enable selective modulation of specific brain circuits without globally affecting synaptic transmission. However, the feasibility of uniquely targeting specific AMPA receptor complexes has not yet been established.

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