Syngap1 Haploinsufficiency Impairs Synaptic Drive and Intrinsic Excitability of Parvalbumin-Positive Interneurons in Mouse Auditory Cortex

Основные понятия

Syngap1 haploinsufficiency in medial ganglionic eminence-derived interneurons, particularly parvalbumin-positive cells, leads to reduced synaptic excitation, decreased intrinsic excitability, and altered dendritic development, which may underlie auditory processing deficits in SYNGAP1-related intellectual disability.

Аннотация

The study examined the impact of embryonic-onset Syngap1 haploinsufficiency, restricted to GABAergic interneurons derived from the medial ganglionic eminence (MGE), on the synaptic and intrinsic properties of parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons in the adult mouse auditory cortex.
Key findings:

Syngap1 haploinsufficiency reduced the excitatory synaptic drive onto both PV+ and SST+ interneurons, with a more pronounced effect on PV+ cells.
PV+ cells from Syngap1 haploinsufficient mice showed decreased intrinsic excitability, including increased action potential threshold and reduced firing in response to current injections.
The intrinsic excitability deficits in PV+ cells were rescued by pharmacological inhibition of Kv1 family of voltage-gated potassium channels, suggesting Syngap1 regulates PV+ cell excitability through this mechanism.
Syngap1 haploinsufficiency selectively affected the dendritic arborization of a subpopulation of PV+ cells (basket cell-short), while the other PV+ subtype (basket cell-broad) and SST+ cells were largely unaffected.

These findings indicate that Syngap1 plays a cell-type specific role in regulating the synaptic drive and intrinsic excitability of PV+ interneurons, which may contribute to the auditory processing deficits observed in SYNGAP1-related intellectual disability.

Статистика

Syngap1 haploinsufficiency in MGE-derived interneurons leads to a significant decrease in the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in both PV+ and SST+ interneurons.
Syngap1 haploinsufficiency decreases the amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in PV+ interneurons, but does not affect miniature IPSCs (mIPSCs).
Thalamocortical evoked AMPA currents are decreased in PV+ interneurons from Syngap1 haploinsufficient mice, while evoked NMDA currents are unaffected.
Syngap1 haploinsufficiency increases the action potential threshold and latency, and decreases the action potential amplitude in PV+ interneurons.
The intrinsic excitability deficits in PV+ interneurons from Syngap1 haploinsufficient mice are rescued by pharmacological inhibition of Kv1 family of voltage-gated potassium channels.

Цитаты

"Syngap1 haploinsufficiency affects the intrinsic properties, overall leading to increased firing threshold, and decreased excitatory synaptic drive of Parvalbumin (PV)+ neurons from Layer IV auditory cortex in adult mice, whilst Somatostatin (SST)+ interneurons were mostly resistant to Syngap1 haploinsufficiency."
"Targeting the Kv1 family of voltage-gated potassium channels was sufficient to rescue PV+ mutant cell-intrinsic properties to wild-type levels."
"Syngap1 plays a specific role in the maturation of PV+ cell intrinsic properties and synaptic drive, and its haploinsufficiency may lead to reduced PV cell recruitment in the adult auditory cortex, which could thus underlie the auditory processing alterations found in SYNGAP1-ID preclinical models and patients."

Ключевые выводы из

Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex

by Francavilla,... в www.biorxiv.org 02-29-2024

https://www.biorxiv.org/content/10.1101/2024.02.27.582362v1

Дополнительные вопросы

How do the cell-type specific effects of Syngap1 haploinsufficiency on PV+ and SST+ interneurons contribute to the altered auditory processing observed in SYNGAP1-related intellectual disability

The cell-type specific effects of Syngap1 haploinsufficiency on PV+ and SST+ interneurons play a crucial role in the altered auditory processing observed in SYNGAP1-related intellectual disability. In the context of the study, it was found that Syngap1 haploinsufficiency primarily affects PV+ interneurons, leading to reduced excitatory synaptic drive and altered intrinsic properties. PV+ interneurons are known to provide perisomatic inhibition to pyramidal cells, playing a key role in shaping cortical activity and modulating auditory information processing. The decreased excitatory synaptic drive and intrinsic excitability of PV+ cells in the auditory cortex could result in disrupted neural circuit function, impacting auditory processing mechanisms such as frequency tuning, sound discrimination, and adaptation to repetitive stimuli. These alterations in PV+ interneurons may contribute to the sensory processing dysfunction and auditory deficits observed in SYNGAP1-related disorders.
On the other hand, SST+ interneurons, another major subtype of cortical inhibitory neurons, were found to be less affected by Syngap1 haploinsufficiency in this study. While SST+ interneurons also play a crucial role in modulating cortical activity and information processing, their synaptic and intrinsic properties remained relatively stable in the presence of Syngap1 deficiency. The differential impact on PV+ and SST+ interneurons highlights the specificity of Syngap1's effects on distinct interneuron subtypes, underscoring the importance of cell-type specific dysfunction in contributing to the overall auditory processing deficits in SYNGAP1-related disorders.

What other molecular pathways, besides Kv1 channels, might Syngap1 regulate to differentially impact the intrinsic properties and synaptic integration of distinct interneuron subtypes

Besides Kv1 channels, Syngap1 may regulate other molecular pathways to differentially impact the intrinsic properties and synaptic integration of distinct interneuron subtypes. One potential pathway that could be involved is the regulation of GABAergic signaling and inhibitory synaptic transmission. Syngap1 has been implicated in the maturation of inhibitory synapses and GABAergic cell migration, suggesting a role in modulating the balance between excitation and inhibition in neural circuits. Alterations in GABAergic signaling pathways could influence the excitability and firing patterns of interneurons, including PV+ and SST+ cells, leading to disruptions in synaptic integration and network activity.
Additionally, Syngap1 may interact with signaling pathways involved in neuronal development and plasticity, such as the Ras-MAPK pathway. Syngap1 is known to regulate synaptic plasticity and dendritic spine morphology in excitatory neurons through its interactions with Ras and other signaling molecules. Dysregulation of these pathways in interneurons could impact their structural and functional properties, affecting their ability to integrate synaptic inputs and modulate network activity.
Furthermore, Syngap1 may modulate calcium signaling pathways that are essential for neuronal excitability and synaptic transmission. Changes in intracellular calcium dynamics can influence the firing properties of interneurons and their responsiveness to excitatory inputs. By regulating calcium signaling pathways, Syngap1 could fine-tune the intrinsic properties of interneurons and their synaptic integration capabilities, contributing to the altered auditory processing observed in SYNGAP1-related disorders.

Could targeting the specific PV+ interneuron subpopulation affected by Syngap1 haploinsufficiency provide a therapeutic avenue to rescue auditory processing deficits in SYNGAP1-related disorders

Targeting the specific PV+ interneuron subpopulation affected by Syngap1 haploinsufficiency could indeed provide a promising therapeutic avenue to rescue auditory processing deficits in SYNGAP1-related disorders. The study findings suggest that Syngap1 plays a specific role in the maturation of PV+ cell intrinsic properties and synaptic drive, leading to reduced excitability and altered firing patterns in these interneurons. By focusing on restoring the function of PV+ interneurons through targeted interventions, it may be possible to mitigate the auditory processing alterations associated with SYNGAP1-related intellectual disability.
One potential therapeutic approach could involve the development of pharmacological agents that specifically enhance the excitability and synaptic integration of PV+ interneurons. For example, modulators of potassium channels, such as Kv1 channel blockers like α-DTX, could be utilized to rescue the intrinsic properties of PV+ cells and restore their normal firing patterns. By restoring the balance of excitation and inhibition in the auditory cortex, these targeted interventions could improve auditory processing and sensory integration in individuals with SYNGAP1-related disorders.
Furthermore, non-pharmacological approaches such as optogenetic stimulation or deep brain stimulation targeted at the affected PV+ interneuron subpopulation could also be explored as potential therapeutic strategies. By directly modulating the activity of PV+ cells in the auditory cortex, it may be possible to enhance their function and restore normal auditory processing mechanisms in SYNGAP1-related disorders. Overall, targeting the specific PV+ interneuron subpopulation affected by Syngap1 deficiency holds promise for developing effective treatments to alleviate auditory deficits and improve cognitive outcomes in individuals with SYNGAP1-related intellectual disability.