Spatially Organized Synaptic Interactions Between Excitatory Stellate Cells and Inhibitory Parvalbumin Interneurons in Layer 2 of the Medial Entorhinal Cortex

Belangrijkste concepten

The synaptic interactions between excitatory stellate cells and inhibitory parvalbumin interneurons in layer 2 of the medial entorhinal cortex are spatially organized, with direct connections between nearby neurons and indirect coordination of inputs at larger spatial scales.

Samenvatting

The study investigates the functional organization of synaptic interactions between excitatory stellate cells (SCs) and inhibitory parvalbumin interneurons (PV+INs) in layer 2 of the medial entorhinal cortex (MEC). The authors used a combination of strategies, including targeted optogenetic activation and simultaneous patch-clamp recordings, to assess the extent and organization of these interactions.

Key findings:

1. SCs and PV+INs have extensive axonal projections within layer 2 of the MEC, suggesting the potential for widespread interactions.
2. Asynchronous wide-field activation of SCs revealed that nearby pairs of PV+INs (< 500 μm apart) often receive coordinated synaptic input, indicating direct connectivity. This coordination drops steeply with increasing distance between the PV+INs.
3. Focal activation of SCs confirmed the local organization of their connections to PV+INs, with pairs of PV+INs receiving common input only when their cell bodies were separated by < 200-400 μm.
4. The spatial organization of SC inputs to PV+INs suggests a modular organization, with distinct boundaries between populations of SCs that provide input to different groups of PV+INs.
5. Activation of PV+INs led to coordinated inhibitory input to nearby pairs of SCs (< 300 μm), but not to pairs of SCs and pyramidal cells, indicating that SCs and pyramidal cells receive inhibition from distinct PV+IN populations.
6. Indirect inhibitory pathways can extend the spatial scale of coordination between PV+INs driven by SCs.

The authors propose that the spatially organized direct and indirect interactions between SCs and PV+INs may support the modular organization of spatial representations in the MEC, with local modules defined by excitatory-inhibitory connectivity and larger-scale coordination across modules.

Statistieken

"Pairs of PV+INs that received coordinated synaptic input from SCs were separated by distances up to 500 µm along the dorsoventral axis and up to 900 µm along the mediolateral axis."
"The maximal dorsoventral and mediolateral extent of the axons of PV+INs was on average > 600 µm, and in both orientations was greater than the corresponding extent of their dendrites."
"Pairs of SCs that received coordinated inhibitory input from PV+INs were separated by < 300 µm along dorsoventral and mediolateral axes."

Citaten

"Interactions between excitatory and inhibitory neurons are critical to computations in cortical circuits but their organization is difficult to assess with standard electrophysiological approaches."
"We find that extensive axonal projections support spatially organized connectivity between stellate cells and parvalbumin interneurons, such that direct connections are often, but not always, shared by nearby neurons, whereas multisynaptic interactions coordinate inputs to neurons with greater spatial separation."
"Our results suggest highly structured and localized synaptic interactions within layer 2 of the MEC as candidates for the organization of spatial representations."

Belangrijkste Inzichten Gedestilleerd Uit

Synaptic interactions between stellate cells and parvalbumin interneurons in layer 2 of the medial entorhinal cortex are organized at the scale of grid cell clusters

by Huang,L.-W.,... om www.biorxiv.org 09-18-2023

https://www.biorxiv.org/content/10.1101/2023.09.18.558206v3

Diepere vragen

How might the spatial organization of SC-PV+IN interactions contribute to the emergence of grid cell firing properties in the MEC?

The spatial organization of interactions between stellate cells (SCs) and parvalbumin interneurons (PV+INs) in the medial entorhinal cortex (MEC) plays a crucial role in the emergence of grid cell firing properties. Grid cells in the MEC exhibit spatially periodic firing properties that are essential for encoding the animal's position in space. The organization of SC-PV+IN interactions at different spatial scales contributes to the generation and maintenance of grid cell firing patterns.

Local Circuit Computations: The close proximity of SCs and PV+INs within a certain spatial range allows for local circuit computations. The direct excitatory-inhibitory synaptic interactions between these neurons at the scale of grid cell clusters facilitate the generation of grid firing fields. This local connectivity pattern enables precise control over the firing properties of grid cells within specific spatial regions.

Modular Organization: The modular organization of SC inputs to PV+INs observed in the study suggests that specific groups of SCs are functionally connected to distinct populations of PV+INs. These modules may correspond to functional units within the grid cell network, where each module contributes to the generation of specific spatial firing patterns. By organizing inputs into modules, the system can encode different spatial representations efficiently.

Spatial Specificity: The spatial extent of coordination between SCs and PV+INs determines the specificity of the input received by grid cells. The localized interactions between SCs and PV+INs ensure that grid cells within a particular region receive coordinated and spatially specific inputs, leading to the formation of grid firing fields with consistent spatial periodicity and orientation.

Integration of Excitation and Inhibition: The balanced interplay between excitation from SCs and inhibition from PV+INs is essential for the generation of grid cell firing patterns. The spatial organization of these interactions ensures that the inhibitory influence from PV+INs is appropriately targeted to regulate the activity of SCs, contributing to the precise firing properties of grid cells.

In summary, the spatial organization of SC-PV+IN interactions in the MEC establishes a framework for the generation of grid cell firing properties by facilitating local circuit computations, modular organization of inputs, spatial specificity of synaptic interactions, and the integration of excitation and inhibition in the grid cell network.

How do the findings from this study on the organization of excitatory-inhibitory circuits in the MEC relate to the functional organization of other cortical circuits involved in spatial information processing?

The findings from this study on the organization of excitatory-inhibitory circuits in the medial entorhinal cortex (MEC) provide insights into the functional organization of other cortical circuits involved in spatial information processing. Understanding the principles governing the interactions between excitatory and inhibitory neurons in the MEC can offer valuable perspectives on how similar circuits operate in other brain regions responsible for spatial computations.

General Principles of Cortical Circuits: The organization of synaptic interactions between stellate cells (SCs) and parvalbumin interneurons (PV+INs) in the MEC reflects fundamental principles of cortical circuits. The spatially organized connectivity between excitatory and inhibitory neurons is a common feature in many cortical areas involved in spatial information processing, such as the hippocampus and neocortex. The modular organization of inputs observed in this study may also be present in other cortical circuits, contributing to the specialization of neuronal ensembles for specific functions.

Spatial Coding Mechanisms: The precise coordination between SCs and PV+INs in the MEC is essential for the generation of grid cell firing patterns. Similar mechanisms of spatial coding and representation may exist in other cortical circuits that encode spatial information, such as place cells in the hippocampus or head direction cells in the retrosplenial cortex. The structured connectivity observed in the MEC may serve as a model for understanding how spatial information is processed and represented in different brain regions.

Network Dynamics: The interactions between excitatory and inhibitory neurons shape the network dynamics and information processing capabilities of cortical circuits. The localized and modular organization of SC-PV+IN interactions in the MEC influences the dynamics of grid cell firing and spatial representation. Similar network dynamics and information processing principles may underlie spatial computations in other cortical circuits involved in navigation, memory, and sensory processing.

Functional Specialization: The functional specialization of excitatory-inhibitory circuits in the MEC for spatial computations highlights the importance of circuit-level organization in supporting specific cognitive functions. Understanding how these circuits are organized and interact can provide insights into the functional specialization of other cortical circuits involved in different cognitive processes, such as attention, decision-making, and motor control.

In conclusion, the findings from this study on the organization of excitatory-inhibitory circuits in the MEC offer valuable insights into the functional organization of cortical circuits involved in spatial information processing, providing a framework for understanding the principles governing neural computations in diverse brain regions.

What are the potential mechanisms that establish the modular organization of SC inputs to PV+INs observed in this study?

The modular organization of stellate cell (SC) inputs to parvalbumin interneurons (PV+INs) observed in the study may be established through a combination of anatomical, developmental, and functional mechanisms that shape the connectivity patterns within the medial entorhinal cortex (MEC). The modular organization of SC inputs to PV+INs reflects a structured and spatially specific arrangement of synaptic interactions, which can be influenced by various factors contributing to the formation of functional modules in the neural circuitry.

Anatomical Connectivity: The anatomical connectivity between SCs and PV+INs may play a critical role in establishing the modular organization of inputs. Specific axonal projections from SCs to distinct populations of PV+INs could create functional modules within the MEC. The spatially organized axonal arborizations of SCs and the dendritic domains of PV+INs may guide the formation of local circuits and define the boundaries of functional modules.

Developmental Patterning: The development of synaptic connections between SCs and PV+INs during early stages of circuit formation could contribute to the modular organization of inputs. Molecular cues, activity-dependent mechanisms, and synaptic plasticity processes may shape the connectivity patterns between SCs and PV+INs, leading to the emergence of functional modules with specific connectivity profiles.

Activity-Dependent Plasticity: The activity of SCs and PV+INs, as well as their interactions during network activity, can influence the establishment of modular organization. Hebbian plasticity mechanisms, such as spike-timing-dependent plasticity, may strengthen synaptic connections between co-active SCs and PV+INs, promoting the formation of functional modules with coordinated activity patterns.

Inhibitory Circuitry: The inhibitory feedback from PV+INs to SCs could also contribute to the modular organization of inputs. The spatially restricted inhibitory influence of PV+INs on SCs may shape the functional boundaries of modules and regulate the activity of SC populations within specific spatial regions.

Network Dynamics: The dynamic interactions between SCs and PV+INs, as well as the network-level activity patterns in the MEC, may influence the modular organization of inputs. Synchronized activity within local circuits, coordinated firing of neuronal ensembles, and the integration of excitatory and inhibitory inputs could establish the functional modules observed in the study.

By integrating these potential mechanisms, the modular organization of SC inputs to PV+INs in the MEC can be understood as a complex interplay of anatomical connectivity, developmental processes, plasticity mechanisms, inhibitory circuit dynamics, and network-level interactions that shape the functional architecture of the neural circuitry involved in spatial computations.