The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome

Sanderson, Jennifer L.; Freund, Ronald K.; Castano, Anna; Benke, Timothy A.; Dell’Acqua, Mark L.

doi:10.1016/j.neuropharm.2022.109271

Cited by 7 publications

(1 citation statement)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5). Despite these channel similarities, NMDARs and L-type VGCCs are differentially regulated and their dysregulation is implicated in different behaviors and diseases (Sanderson et al, 2022; Laryushkin et al, 2021; Mielnik et al, 2021; Myers et al, 2019; Ortner & Striessnig, 2015; Q. Zhou & Sheng, 2013).…”

Section: Discussionmentioning

confidence: 99%

Sex-specific mechanisms underlie long-term potentiation at hippocampus-nucleus accumbens synapses

Copenhaver,

LeGates

2024

Preprint

View full text Add to dashboard Cite

Sex differences have complicated our understanding of the neurobiological basis of many behaviors that are key for survival. As such, continued elucidation of the similarities and differences between sexes is necessary in order to gain insight into brain function and vulnerability. The connection between the hippocampus (Hipp) and nucleus accumbens (NAc) is a crucial site where modulation of neuronal activity mediates reward-related behavior. Our previous work demonstrated that long-term potentiation (LTP) of Hipp-NAc synapses is rewarding, and that mice can make learned associations between LTP of these synapses and the contextual environment in which LTP occurred. Here, we investigate sex differences in the mechanisms underlying Hipp-NAc LTP using whole-cell electrophysiology and pharmacology. We found that males and females display similar magnitudes of Hipp-NAc LTP which occurs postsynaptically. However, LTP in females requires L-type voltage-gated Ca2+channels (VGCC) for postsynaptic Ca2+influx, while males rely on NMDA receptors (NMDAR). Additionally, females require estrogen receptor α (ERα) activity for LTP while males do not. These differential mechanisms converge as LTP in both sexes depends on CAMKII activity and occurs independently of dopamine-1 receptor (D1R) activation. Our results have elucidated sex-specific molecular mechanisms for LTP in an integral excitatory pathway that mediates reward-related behaviors, emphasizing the importance of considering sex as a variable in mechanistic studies. Continued characterization of sex-specific mechanisms underlying plasticity will offer novel insight into the neurophysiological basis of behavior, with significant implications for understanding how diverse processes mediate behavior and contribute to vulnerability to developing psychiatric disorders.SIGNIFICANCE STATEMENTStrengthening of Hipp-NAc synapses drives reward-related behaviors. Male and female mice have similar magnitudes of long-term potentiation (LTP) and both sexes have a predicted postsynaptic locus of plasticity. Despite these similarities, we illustrate here that sex-specific molecular mechanisms are used to elicit LTP. Given the bidirectional relationship between Hipp-NAc synaptic strength in mediating reward-related behaviors, the use of distinct molecular mechanisms may explain sex differences observed in stress susceptibility or response to rewarding stimuli. Discovery and characterization of convergent sex differences provides mechanistic insight into the sex-specific function of Hipp-NAc circuitry and has widespread implications for circuits mediating learning and reward-related behavior.

show abstract

Section: Discussionmentioning

confidence: 99%

Sex-specific mechanisms underlie long-term potentiation at hippocampus-nucleus accumbens synapses

Copenhaver,

LeGates

2024

Preprint

View full text Add to dashboard Cite

show abstract

Anchored PKA synchronizes adrenergic phosphoregulation of cardiac Cav1.2 channels

Wang,

Chen,

et al. 2024

Journal of Biological Chemistry

View full text Add to dashboard Cite

Effects of exposure to different frequencies of electromagnetic fields on long-term potentiation in rat hippocampal CA1 region through intracellular Ca2+ concentration

Zheng,

Song,

Wei

et al. 2024

AIP Advances

View full text Add to dashboard Cite

Long-term potentiation (LTP) in the Schaffer-CA1 region of the hippocampus is closely related to learning and memory. Magnetic stimulation, as an effective physical means of regulating synaptic plasticity, has received widespread attention. However, research on the mechanism of the effect of different frequencies of magnetic fields (MFs) on LTP is relatively scarce. This article focuses on Ca2+, Na+, K+, NMDA receptors, and AMPA receptors that play important roles in the process of MF regulation of LTP. A combined electrophysiological and pharmacological approach was used to identify Ca2+ as a key factor in the modulation of LTP by MFs of different frequencies. Subsequently, further experiments revealed that low levels of intracellular Ca2+ concentration ([Ca2+]i) intensified the inhibition of low-frequency MFs on LTP, while high levels of [Ca2+]i enhanced the promotion effect of high-frequency MFs on LTP, indicating a positive correlation between [Ca2+]i levels and MF regulation of LTP levels. The research results of this article may help explore the deeper relationship between different frequencies of MFs and synaptic plasticity, and they also have a certain reference value for magnetic stimulation therapy in the treatment of neurological diseases related to LTP injury or learning and memory deficits.

show abstract

The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome

Cited by 7 publications

References 104 publications

Sex-specific mechanisms underlie long-term potentiation at hippocampus-nucleus accumbens synapses

Sex-specific mechanisms underlie long-term potentiation at hippocampus-nucleus accumbens synapses

Anchored PKA synchronizes adrenergic phosphoregulation of cardiac Cav1.2 channels

Effects of exposure to different frequencies of electromagnetic fields on long-term potentiation in rat hippocampal CA1 region through intracellular Ca2+ concentration

Contact Info

Product

Resources

About