Chlorogenic Acid Decreases Glutamate Release from Rat Cortical Nerve Terminals by P/Q-Type Ca2+ Channel Suppression: A Possible Neuroprotective Mechanism

The glutamatergic neurotransmitter system has received substantial attention in research on the pathophysiology and treatment of neurological disorders. The study investigated the effect of the polyphenolic compound chlorogenic acid (CGA) on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). CGA inhibited 4-aminopyridine (4-AP)-induced glutamate release from synaptosomes. This inhibition was prevented in the absence of extracellular Ca2+ and was associated with the inhibition of 4-AP-induced elevation of Ca2+ but was not attributed to changes in synaptosomal membrane potential. In line with evidence observed through molecular docking, CGA did not inhibit glutamate release in the presence of P/Q-type Ca2+ channel inhibitors; therefore, CGA-induced inhibition of glutamate release may be mediated by P/Q-type Ca2+ channels. CGA-induced inhibition of glutamate release was also diminished by the calmodulin and Ca2+/calmodilin-dependent kinase II (CaMKII) inhibitors, and CGA reduced the phosphorylation of CaMKII and its substrate, synapsin I. Furthermore, pretreatment with intraperitoneal CGA injection attenuated the glutamate increment and neuronal damage in the rat cortex that were induced by kainic acid administration. These results indicate that CGA inhibits glutamate release from cortical synaptosomes by suppressing P/Q-type Ca2+ channels and CaMKII/synapsin I pathways, thereby preventing excitotoxic damage to cortical neurons.

A Multiscale View of the Mechanisms Underlying Ketamine’s Antidepressant Effects: An Update on Neuronal Calcium Signaling

Major depressive disorder (MDD) is a debilitating disease characterized by depressed mood, loss of interest or pleasure, suicidal ideation, and reduced motivation or hopelessness. Despite considerable research, mechanisms underlying MDD remain poorly understood, and current advances in treatment are far from satisfactory. The antidepressant effect of ketamine is among the most important discoveries in psychiatric research over the last half-century. Neurobiological insights into the ketamine’s effects have shed light on the mechanisms underlying antidepressant efficacy. However, mechanisms underlying the rapid and sustained antidepressant effects of ketamine remain controversial. Elucidating such mechanisms is key to identifying new therapeutic targets and developing therapeutic strategies. Accumulating evidence demonstrates the contribution of the glutamatergic pathway, the major excitatory neurotransmitter system in the central nervous system, in MDD pathophysiology and antidepressant effects. The hypothesis of a connection among the calcium signaling cascade stimulated by the glutamatergic system, neural plasticity, and epigenetic regulation of gene transcription is further supported by its associations with ketamine’s antidepressant effects. This review briefly summarizes the potential mechanisms of ketamine’s effects with a specific focus on glutamatergic signaling from a multiscale perspective, including behavioral, cellular, molecular, and epigenetic aspects, to provide a valuable overview of ketamine’s antidepressant effects.

Neurotransmitter System-Targeting Drugs Antagonize Growth of the Q Fever Agent, Coxiella burnetii, in Human Cells

Coxiella burnetii causes the debilitating disease Q fever in humans. This infection is difficult to treat with current antibiotics and can progress to long-term, potentially fatal infection in immunocompromised individuals or when treatment is delayed.

Reductions in midbrain GABAergic and dopamine neuron markers are linked in schizophrenia

Reductions in the GABAergic neurotransmitter system exist across multiple brain regions in schizophrenia and encompass both pre- and postsynaptic components. While reduced midbrain GABAergic inhibitory neurotransmission may contribute to the hyperdopaminergia thought to underpin psychosis in schizophrenia, molecular changes consistent with this have not been reported. We hypothesised that reduced GABA-related molecular markers would be found in the midbrain of people with schizophrenia and that these would correlate with dopaminergic molecular changes. We hypothesised that downregulation of inhibitory neuron markers would be exacerbated in schizophrenia cases with high levels of neuroinflammation. Eight GABAergic-related transcripts were measured with quantitative PCR, and glutamate decarboxylase (GAD) 65/67 and GABAA alpha 3 (α3) (GABRA3) protein were measured with immunoblotting, in post-mortem midbrain (28/28 and 28/26 control/schizophrenia cases for mRNA and protein, respectively), and analysed by both diagnosis and inflammatory subgroups (as previously defined by higher levels of four pro-inflammatory cytokine transcripts). We found reductions (21 – 44%) in mRNA encoding both presynaptic and postsynaptic proteins, vesicular GABA transporter (VGAT), GAD1, and parvalbumin (PV) mRNAs and four alpha subunits (α1, α2, α3, α5) of the GABAA receptor in people with schizophrenia compared to controls (p < 0.05). Gene expression of somatostatin (SST) was unchanged (p = 0.485). We confirmed the reduction in GAD at the protein level (34%, p < 0.05). When stratifying by inflammation, only GABRA3 mRNA exhibited more pronounced changes in high compared to low inflammatory subgroups in schizophrenia. GABRA3 protein was expressed by 98% of tyrosine hydroxylase-positive neurons and was 23% lower in schizophrenia, though this did not reach statistical significance (p > 0.05). Expression of transcripts for GABAA receptor alpha subunits 2 and 3 (GABRA2, GABRA3) were positively correlated with tyrosine hydroxylase (TH) and dopamine transporter (DAT) transcripts in schizophrenia cases (GABRA2; r > 0.630, GABRA3; r > 0.762, all p < 0.001) but not controls (GABRA2; r < − 0.200, GABRA3; r < 0.310, all p > 0.05). Taken together, our results support a profound disruption to inhibitory neurotransmission in the substantia nigra regardless of inflammatory status, which provides a potential mechanism for disinhibition of nigrostriatal dopamine neurotransmission.

Imaging the Pathophysiology of Essential Tremor—A Systematic Review

Background: The pathophysiology underlying essential tremor (ET) still is poorly understood. Recent research suggests a pivotal role of the cerebellum in tremor genesis, and an ongoing controversy remains as to whether ET constitutes a neurodegenerative disorder. In addition, mounting evidence indicates that alterations in the gamma-aminobutyric acid neurotransmitter system are involved in ET pathophysiology. Here, we systematically review structural, functional, and metabolic neuroimaging studies and discuss current concepts of ET pathophysiology from an imaging perspective.Methods: We conducted a PubMed and Scopus search from 1966 up to December 2020, entering essential tremor in combination with any of the following search terms and their corresponding abbreviations: positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and gamma-aminobutyric acid (GABA).Results: Altered functional connectivity in the cerebellum and cerebello-thalamico-cortical circuitry is a prevalent finding in functional imaging studies. Reports from structural imaging studies are less consistent, and there is no clear evidence for cerebellar neurodegeneration. However, diffusion tensor imaging robustly points toward microstructural cerebellar changes. Radiotracer imaging suggests that the dopaminergic axis is largely preserved in ET. Similarly, measurements of nigral iron content and neuromelanin are unremarkable in most studies; this is in contrast to Parkinson's disease (PD). PET and MRS studies provide limited evidence for cerebellar and thalamic GABAergic dysfunction.Conclusions: There is robust evidence indicating that the cerebellum plays a key role within a multiple oscillator tremor network which underlies tremor genesis. However, whether cerebellar dysfunction relies on a neurodegenerative process remains unclear. Dopaminergic and iron imaging do not suggest a substantial overlap of ET with PD pathophysiology. There is limited evidence for alterations of the GABAergic neurotransmitter system in ET. The clinical, demographical, and genetic heterogeneity of ET translates into neuroimaging and likely explains the various inconsistencies reported.

Hostility in medication-resistant major depression and comorbid generalized anxiety disorder is related to increased hippocampal–amygdala 5-HT2A receptor density

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are severe and difficult-to-treat psychiatric illnesses with high rates of comorbidity. Although both disorders are treated with serotonergic based psychotropic agents, little is known on the influence of the serotonergic neurotransmitter system on the occurrence of comorbid GAD when clinically depressed. To investigate this poorly understood clinical question, we examined the involvement of frontolimbic post-synaptic 5-HT2A receptors in 20 medication-resistant depressed (MRD) patients with half of them diagnosed with comorbid GAD with 123I-5-I-R91150 SPECT. To explore whether 5-HT2A receptor-binding indices (BI) associated with comorbid GAD could be related to distinct psychopathological symptoms, all were assessed with the symptom Checklist-90-Revised (SCL-90-R). MRD patients with comorbid GAD displayed significantly higher 5-HT2A receptor BI in the hippocampal–amygdala complex, compared to MRD patients without GAD. Correlation analyses revealed that the 5-HT2A receptor BI in these areas were significantly related to the SCL-90-R subscale hostility (HOS), especially for those MRD patients with comorbid GAD. Comorbid MRD-GAD may be characterized with increased hippocampal–amygdala 5-HT2A receptor BI which could represent enhanced levels in hostility in such kinds of patients. Adapted psychotherapeutic interventions may be warranted.

Roles of the Functional Interaction between Brain Cholinergic and Dopaminergic Systems in the Pathogenesis and Treatment of Schizophrenia and Parkinson’s Disease

Most physiologic processes in the brain and related diseases involve more than one neurotransmitter system. Thus, elucidation of the interaction between different neurotransmitter systems could allow for better therapeutic approaches to the treatments of related diseases. Dopaminergic (DAergic) and cholinergic neurotransmitter system regulate various brain functions that include cognition, movement, emotion, etc. This review focuses on the interaction between the brain DAergic and cholinergic systems with respect to the pathogenesis and treatment of schizophrenia and Parkinson’s disease (PD). We first discussed the selection of motor plans at the level of basal ganglia, the major DAergic and cholinergic pathways in the brain, and the receptor subtypes involved in the interaction between the two signaling systems. Next, the roles of each signaling system were discussed in the context of the negative symptoms of schizophrenia, with a focus on the α7 nicotinic cholinergic receptor and the dopamine D1 receptor in the prefrontal cortex. In addition, the roles of the nicotinic and dopamine receptors were discussed in the context of regulation of striatal cholinergic interneurons, which play crucial roles in the degeneration of nigrostriatal DAergic neurons and the development of L-DOPA-induced dyskinesia in PD patients. Finally, we discussed the general mechanisms of nicotine-induced protection of DAergic neurons.