mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks

Abstract

The newly evolved circuits in layer III of primate dorsolateral prefrontal cortex (dlPFC) generate the neural representations that subserve working memory. These circuits are weakened by increased cAMP-K+ channel signaling, and are a focus of pathology in schizophrenia, aging, and Alzheimer's disease. Cognitive deficits in these disorders are increasingly associated with insults to mGluR3 metabotropic glutamate receptors, while reductions in mGluR2 appear protective. This has been perplexing, as mGluR3 has been considered glial receptors, and mGluR2 and mGluR3 have been thought to have similar functions, reducing glutamate transmission. We have discovered that, in addition to their astrocytic expression, mGluR3 is concentrated postsynaptically in spine synapses of layer III dlPFC, positioned to strengthen connectivity by inhibiting postsynaptic cAMP-K+ channel actions. In contrast, mGluR2 is principally presynaptic as expected, with only a minor postsynaptic component. Functionally, increase in the endogenous mGluR3 agonist, N-acetylaspartylglutamate, markedly enhanced dlPFC Delay cell firing during a working memory task via inhibition of cAMP signaling, while the mGluR2 positive allosteric modulator, BINA, produced an inverted-U dose-response on dlPFC Delay cell firing and working memory performance. These data illuminate why insults to mGluR3 would erode cognitive abilities, and support mGluR3 as a novel therapeutic target for higher cognitive disorders.

Alterations of Astrocytes in the Context of Schizophrenic Dementia

“…In schizophrenia, there is a decreased expression of GLT-1 in the hippocampus of postmortem brain samples (Shan et al, 2013) and prefrontal cortex of genotyped patients (Spangaro et al, 2012). The blockade of GLT-1 increased the tonic activation of presynaptic metabotropic glutamate receptors (mGluRs) (Fleming et al, 2011), some of which protect neurons from excessive excitability and regulate the functioning of working memory of rhesus macaques (Jin et al, 2018). It was also noted that agonist mGluR2/3 ameliorates symptoms of schizophrenic psychoses (Segnitz et al, 2009).…”

Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia

“…134,145 In contrast, mGluR2 are localized presynaptically, where they inhibit glutamate release. 146 Another critical regulator of feedforward cAMP–calcium signaling in newly evolved dlPFC layer III microcircuits is the phosphodiesterase, PDE4A, which catabolizes cAMP and is anchored to the spine apparatus by the scaffolding protein Disrupted in Schizophrenia (DISC1). 147,148 Importantly, inflammation can reduce PDE4A actions and detach it from DISC1 via MAP kinase-activated protein kinase 2 (MK2) signaling.…”

Group II metabotropic glutamate receptors modulate sound evoked and spontaneous activity in the mouse inferior colliculus

“…For example, Tyszkiewicz et al (2004) demonstrated that group II mGluR activation increased post-synaptic glutamate ionotropic NMDA receptor currents in dissociated rat prefrontal cortex pyramidal neurons. As we learn more about receptor subcellular localization, and expand efforts to disambiguate subtype specific roles (mGluR2 versus mGluR3; Copeland et al, 2012;Jin et al, 2018;Wood et al, 2018), it should be possible to better explain how group II mGluRs can exert both inhibitory and excitatory actions. It remains to be tested whether in the mouse IC postsynaptic receptors may be a major mGluR2/3 component.…”