Alzheimer's disease is a neurodegenerative disease. Recently, alterations in the mesolimbic system have been described, especially in the nucleus accumbens (nAc). We found that intracellular accumulation of Aβ was higher in neurons of the APP/PS1 mice at 10 and 15 days in vitro . At 15 days in vitro (DIV), APP/PS1 accumbal neurons showed alterations in synaptic transmission and neuronal excitability. Specifically, there was an increase in AMPAergic synaptic currents, which was sensitive to the application of NASPM, suggesting a critical role for calcium-permeable AMPA receptors (CP-AMPARs). Our study indicates that this neuronal culture model accurately replicates alterations in the early stages of AD.

Alzheimer’s disease (AD) is increasingly associated with early circuit dysfunction preceding cognitive decline, including neuronal hyperactivity and neuropsychiatric symptoms linked to mesolimbic pathways. The nucleus accumbens (nAc), a central regulator of reward and motivational processing, exhibits early alterations in excitation/inhibition balance in patients and experimental models; however, the synaptic mechanisms underlying this vulnerability remain unclear. Here, we identify a cell-type-specific synaptic mechanism in the nAc linking early intraneuronal Aβ accumulation to circuit dysfunction. Using a double transgenic APP/PS1 mouse model expressing tdTomato in dopamine D1 receptor-positive medium spiny neurons (D1R+ MSNs), we show that long-term depression (LTD) is selectively impaired in D1R+ MSNs despite comparable Aβ levels across neuronal subtypes, revealing differential functional vulnerability. This deficit is associated with an increased contribution of calcium-permeable AMPA receptors (CP-AMPARs) and a disruption of mGluR1/5-dependent LTD, a key mechanism regulating AMPAR trafficking. Pharmacological blockade of CP-AMPARs restores synaptic depression, indicating altered receptor composition as a central feature of this phenotype. These synaptic alterations co-occur with reduced dopaminergic signaling and selective behavioral changes characterized by increased consumption of palatable reward and altered baseline context preference, while associative learning remains preserved. Together, these findings reveal a postsynaptic mechanism in which impaired mGluR-dependent plasticity permits persistent CP-AMPAR signaling, shifting synaptic balance toward increased excitatory drive and mesolimbic hyperactivity in AD.

Background: Intracellular amyloid-beta oligomers (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer’s disease (AD). However, to date, no mechanism linking them has been reported. Methods: Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neurons in vitro , ex vivo and in vivo. Results: Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-related fluorescence changes indicated that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current-clamp recordings suggested that iAβo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. Conclusion: These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

Background: Intracellular amyloid-beta oligomers (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer’s disease (AD). However, to date, no mechanism linking them has been reported. Methods: Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neurons in vitro, ex vivo and in vivo . Results: Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-related fluorescence changes indicated that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current-clamp recordings suggested that iAβo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. Conclusion: These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

Hypothalamic tanycytes have traditionally been viewed as metabolic sensors, structural components of hypothalamic barriers, and transporters of circulating signals. However, accumulating evidence indicates that they also translate metabolic, hormonal, and inflammatory inputs into bioactive signals that coordinate communication with neurons, glia, blood vessels, and cerebrospinal fluid. Here, we introduce the term tanykines to describe bioactive molecules whose extracellular availability depends on their regulated generation, release, processing, or bioactivation by tanycytes and that modify tanycyte function or other target cells. We propose a mechanism-based taxonomy comprising: (i) primary tanykines, directly generated and released by tanycytes, including ATP, lactate, β-hydroxybutyrate, prostaglandin E₂, and VEGF-A; (ii) secondary processed tanykines, generated extracellularly from a primary tanykine, exemplified by ATP-derived adenosine; and (iii) bioactivated tanykines, produced through tanycyte-dependent transformation of a transported precursor, exemplified by T4-to-T3 conversion. We further distinguish established, probable, and candidate or disputed tanykines according to tanycytic origin, regulated extracellular availability, target-cell identity, mechanism of action, and physiological causality. This framework separates tanykines from molecules merely sensed, transported, or expressed by tanycytes and reframes these cells as context-dependent signal generators coordinating metabolic and neuroendocrine homeostasis.