Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

Abstract

Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1 5-HT À / À mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while a1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT 1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1 5-HT À / À mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior.

Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target

“…Thus we hypothesized that histone H3 hyperacetylation might be an underlying mechanism contributing to enhanced glutamatergic gene expression in heroin users. We focused on GRIA1 since this gene encodes the GRIA1 AMPA receptor subunit that is highly implicated in drug addiction behavior and synaptic plasticity (14–17). Interestingly, both pan-AcH3 (r=0.41, p=0.0316; Figure 3A) and H3K27ac (r=0.50, p=0143; Figure 3B) showed a positive correlation with GRIA1 expression in heroin but not in control subjects.…”

“…The AMPA glutamate receptor subunit Gria1 specifically has been implicated in substance use (14, 15, 20, 21) and related neuropsychiatric disorders (17). Our data now provide new insight highlighting the important contribution of specific acetylation disturbances related to transcriptional alterations of striatal GRIA1 in human heroin abusers that is dynamically regulated with repeated use of the drug.…”

FGF‐2 deficiency causes dysregulation of Arhgef6 and downstream targets in the cerebral cortex accompanied by altered neurite outgrowth and dendritic spine morphology

“…In the Tail Suspension Test mice were suspended by their tails with adhesive tape attached to a hook, which was coupled to a computer‐assisted energy measurement (Bioseb, Chaville, France). A test session lasted 6 min, during which the time spent immobile as well as the latency to become immobile were determined (Vogt et al, 2008; Weber et al, 2015).…”

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ25‐35‐induced anxiety and cognitive deficits in a mouse model

“…45 Evidence also suggests that a dysregulation of the serotonergic system induces anxiety-like behaviors. 46 Previous immunohistochemical evidence also suggests that serotonergic fibers have dense terminals in the basolateral complex of the amygdala. 47 In addition, HDACi such as valproic acid (VPA) and trichostatin A (TSA) modulate the activity of serotonergic neurons.…”

“…Early evidence shows marked serotonergic neuron loss, predominantly in the raphe nucleus, in patients with AD . Evidence also suggests that a dysregulation of the serotonergic system induces anxiety‐like behaviors . Previous immunohistochemical evidence also suggests that serotonergic fibers have dense terminals in the basolateral complex of the amygdala .…”