Recent studies implicate astrocytes in Alzheimer’s disease (AD); however, their role in pathogenesis is poorly understood. Astrocytes have well-established functions in supportive functions such as extracellular ionic homeostasis, structural support, and neurovascular coupling. However, emerging research on astrocytic function in the healthy brain also indicates their role in regulating synaptic plasticity and neuronal excitability via the release of neuroactive substances named gliotransmitters. Here, we review how this “active” role of astrocytes at synapses could contribute to synaptic and neuronal network dysfunction and cognitive impairment in AD.

Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene for which no therapies are available. HTT mutation causes protein misfolding and aggregation, preferentially affecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genes and neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understanding the interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigated the role of protein kinase CK2α’, a kinase upregulated in MSNs in HD and previously associated with Parkinson’s disease (PD), in the regulation of neuroinflammation and synaptic function in HD. We used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α’ (zQ175:CK2α’^(±)). CK2α’ haploinsufficiency in zQ175 mice resulted in decreased levels of pro-inflammatory cytokines, HTT aggregation, astrogliosis and transcriptional alterations of synaptic genes related to glutamatergic signaling. zQ175:CK2α’^(±) mice also presented increased frequency of striatal miniature excitatory postsynaptic currents (mEPSCs), an indicator of synaptic activity, and improved motor coordination compared to zQ175 mice. Neuropathological and phenotypic changes mediated by CK2α’ were connected to alpha-synuclein (α-syn) dysregulation and correlated with differences in α-syn serine 129 phosphorylation (pS129-α-syn), a post-translational modification involved in α-synucleinopathy and shown to be regulated by CK2 in PD. pS129-α-syn was increased in the nuclei of MSNs in zQ175 mice and in the striatum of patients with HD, and it decreased in zQ175:CK2α’^(±) mice. Collectively, our data established a novel connection between CK2α’, neuroinflammation and synaptic gene dysregulation with synucleinopathy in HD and suggested common molecular mechanisms of neurodegeneration between HD and PD. Our results also support CK2α’ inhibition as a potential therapeutic strategy to modulate neuronal function and neuroprotection in HD.

Accumulating evidence has revealed the existence of functional astrocyte-neuron communication based on the ability of astrocytes to respond to neurotransmitters and release gliotransmitters. However, little is known about how other signaling molecules, such as hormones, impact astrocyte function. Estradiol (E2) is an important hormone known to regulate neuronal activity, synaptic transmission, plasticity, and animal behavior. However, whether E2 specifically signals to astrocytes in situ and the functional consequences on astrocyte-neuron communication remain unknown. Therefore, we investigated the impact of estradiol on astrocyte activity and astrocyte-neuron communication in the mouse hippocampus. Using an RNAscope approach, we determined that estrogen receptors (ERα and ERβ) are expressed in astrocytes in both female and male mice. In both sexes, confocal imaging of hippocampal slices determined that astrocytes respond to locally applied E2 with calcium elevations. In pyramidal neurons, slow inward currents (SICs) are mediated by the activation of extrasynaptic NMDA receptors and indicate gliotransmission. Electrophysiological recordings of hippocampal neurons determined that E2 increases the frequency, but not the amplitude, of SICs. We also recorded excitatory synaptic transmission evoked by Schaffer collateral stimulation. Here, only in females, did E2 produce a reduction in excitatory synaptic transmission. The E2-induced effects on the astrocyte calcium signal and gliotransmission were prevented by the broad estrogen receptor antagonist ICI 182,780. Taken together, these results demonstrate the existence of estradiol-mediated astrocyte-neuron communication in both female and male mice. They reveal that E2 can signal to astrocytes and, through this signaling, E2 may regulate neuronal activity and synaptic transmission.

Alzheimer’s disease (AD) is classically defined by central hallmarks such as amyloid-beta plaques, tau hyperphosphorylation, and synaptic failure. However, mounting evidence suggests that dysfunction outside the brain, particularly in the peripheral nervous system, may also play a significant role in disease progression. The adrenal medulla—a key regulator of systemic neurotransmission and stress response—has received little attention in this context. In this study, we investigated whether chromaffin cells (CCs) from the triple transgenic AD mouse model (3xTg) exhibit functional alterations that could contribute to peripheral neurochemical imbalance. Using electrophysiology, high-resolution amperometry, and neurotransmitter quantification, we identified early and progressive defects in CC function. Remarkably, even at two months of age—prior to cognitive decline—3xTg CCs showed impaired exocytosis, reduced vesicle release, and slower fusion pore kinetics. These changes were accompanied by diminished sodium (INa), calcium (ICa), and nicotinic (IACh) currents, compromising CC excitability. With age, a shift toward increased potassium (IK) currents and enhanced catecholamine secretion may reflect compensatory adaptations aimed at preserving output. These functional deficits were paralleled by structural remodeling of the actin cytoskeleton and systemic neurotransmitter disturbances. Noradrenaline levels increased in both plasma and brain, while dopamine decreased peripherally but paradoxically increased in the prefrontal cortex and hippocampus. Serotonin levels consistently declined across compartments. These imbalances correlated with altered behavior: 3xTg mice displayed increased exploration of exposed areas and heightened behavioral despair, pointing to anxiety- and depression-like phenotypes. Together, our findings identify the adrenal medulla as a previously underrecognized site of early catecholaminergic dysregulation in AD. The observed associations between peripheral CC dysfunction, systemic neurotransmitter imbalance, and behavioral changes point to a potential link between peripheral neuroendocrine alterations and central disease features. These results broaden the current understanding of AD pathophysiology and support the adrenal medulla as a promising candidate for further investigation as a therapeutic target and source of peripheral biomarkers.

At cellular and circuit levels, drug addiction is considered a dysregulation of synaptic plasticity. In addition, dysfunction of the glutamate transporter 1 (GLT‐1) in the nucleus accumbens (NAc) has also been proposed as a mechanism underlying drug addiction. However, the cellular and synaptic impact of GLT‐1 alterations in the NAc remain unclear. Here we show in the NAc that 10 days withdraw after 5 days treatment with cocaine or amphetamine decreases GLT‐1 expression in astrocytes, which results in the prolongation of the excitatory postsynaptic potential (EPSP) decay kinetics in D1 receptor‐containing medium spiny neurons (D1R‐MSNs). Using the spike timing dependent plasticity (STDP) paradigm, we found that enlargement of EPSP duration results in switching the LTP elicited in control animals to LTD in psychostimulant‐treated mice. In contrast to D1‐MSNs, D2‐MSNs did not display changes in EPSP kinetics and synaptic plasticity. Notably, the psychostimulant‐induced synaptic transmission and synaptic plasticity effects were absent in IP3R2 ^−/− mice, which lack astrocyte calcium signal, but were mimicked by the selective astrocytes stimulation with DREADDs. Finally, ceftriaxone, which upregulates GLT‐1, restored normal GLT‐1 function, EPSP kinetics, and synaptic plasticity in psychostimulant‐treated mice. Therefore, we propose that cocaine and amphetamine increase dopaminergic levels in the NAc, which stimulates astrocytes and downregulates the GLT‐1. The decreased GLT‐1 function prolonged the EPSP kinetics, leading to the modulation of the STDP, transforming the LTP observed in control animals into LTD in psychostimulant‐treated mice. Present work reveals a novel mechanism underlying the synaptic plasticity changes induced by these drugs of abuse.

Background: Huntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene for which no therapies are available. This mutation causes HTT protein misfolding and aggregation, preferentially affecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genes and neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understanding the interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigated whether protein kinase CK2α’, a kinase upregulated in MSNs in HD and previously associated with Parkinson’s disease (PD), participates in the regulation of neuroinflammation and synaptic function during HD progression. Methods: We used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α’. We performed neuropathological analyses using immunohistochemistry, cytokine proteome profiling, RNA-seq analyses in the striatum, electrophysiological recordings, and behavioral analyses. We also used the murine immortalized striatal cell lines ST Hdh ^Q7 and ST Hdh ^Q111 and studied the expression of various synaptic genes dysregulated by CK2α’. Results: We showed that CK2α’ haploinsufficiency in zQ175 mice ameliorated neuroinflammation, HTT aggregation, transcriptional alterations, excitatory synaptic transmission, and motor coordination deficits. RNA-seq analyses also revealed a connection between α-syn, a protein associated with PD, and the transcriptional perturbations mediated by CK2α’ in HD. We also found increased α-syn serine 129 phosphorylation (pS129-α-syn), a post-translational modification linked to α-synucleinopathy, in the nuclei of MSNs in zQ175 mice and in patients with HD. Levels of pS129-α-syn were ameliorated in zQ175 lacking one allele of CK2α’. Conclusions: Our data demonstrated that CK2α’ contributes to transcriptional dysregulation of synaptic genes and neuroinflammation in zQ175 mice and its depletion improved several HD-like phenotypes in this mouse model. These effects were related to increased phosphorylation of S129-α-syn in the striatum of HD mice, suggesting that CK2α’ contributes to worsening HD by mediating synucleinopathy. Our study highlights a possible convergent mechanism of neurodegeneration between HD and PD and suggests targeting CK2α’ as a potential therapeutic strategy to ameliorate synaptic dysfunction in HD as well as other neurodegenerative diseases.