Finding Connections Between Inhibitory Neurons
Recently there has been an increase in connectnomic studies, with the ultimate goal of determining the wiring diagram of the brain. However, many of these studies tend to focus on excitatory neurons. Either these studies focus on excitation-to-excitation, inhibition-to-excitation, or excitation-to-inhibition. This focus often ignores inhibition-to-inhibition connections between inhibitory neurons. Fortunately several papers focusing on the connections between inhibitory neurons are becoming more common, and scientists can now answer how inhibitory interneurons connected to each other with very high resolution. Specifically one such study Parvalbumin+interneurons obey unique connectivity rules and establish a powerful lateral-inhibition microcircuit in dentate gyrus by Dr. Claudia Espinosa, Dr. Segundo Guzman, Dr. Xiaomin Zhang, and Dr. Peter Jonas, focused on PV cells in the dentate gyrus.
Parvalbumin cells (PV) cells are a type of inhibitory cell found all over the brain, and these neurons primarily use the inhibitory neurotransmitter GABA. Here the study focuses exclusively on what are the connections between PV cells and the excitatory granular cells(GC).They examined many different possible connections between PV and GC neurons. Using careful and tedious electrophysiological experiments they were able to reliably tell if two neurons were connected by either an inhibitory synapse, excitatory synapse, or gap junction. Specifically to do this, they would use whole cell patch clamp recording from 8 cells in the dentate gyrus at a time. They would use a voltage clamp to hold the membrane voltage constant and measure weather this cause a postsynaptic inhibitory current or excitatory current in the cells. Because there were 8 cells and 3 connection types there are 9098 different possible connections. These different connection possibilities are known as motifs and plotted the relative and absolute abundance of the motifs in figure 5 of their paper. Furthermore figure 5b compared the real network to simulated random networks. I have attached a screenshot of the figure below.
As many previous studies have shown, they did find that a single PV cells connects to many GC cells [motif 9], and that many different GC cells connect to a single PV cell [motif 7]. This means that a single PV cell activity can laterally inhibit many GC cells. This gives the PV cell a strong local inhibitory reach. Yet there study did not stop there, they also found that PV cells are highly locally connected with each other. PV cells form two types of connections with each others. First they commonly connected with gap junctions [motif 2] which are electrical synapses that share the cytoplasm between cells. This allows the electrical signals to diffuse between cells. Thus if one cell is spiking, the spikes can be recorded in the electrically coupled cells. However, PV cells also form recurrent inhibitory connections between each other. This means that cell 1 inhibits cell 2 and likewise cell 2 inhibits cell 1. Interestingly, this means that if cell 1 is spiking, cell 2 is off, and if cell 2 is spiking cell 1 is off. However to complicate things, Recurrent inhibition is often found with gap junctions, and gap junctions work in the opposite fashion, i.e cell 1 is spiking then cell 2 is also spiking and vise versa.
The fact that these networks contain both inhibition and gap junctions is key because other studies, including one from Zochowski et al. have shown that inhibitory networks with gap junctions can form synchronized activity across the network, or can for highly complex heterogeneous states, that can process asymmetries in inputs into the inhibitory network. Thus the presence of highly recurrent connections and gap junctions in PV cells, likely suggests that they are helpful in processing information on the microcircuit level.
Author: Alexander White
Source: Claudia Espinoza, Segundo Jose Guzman, Xiaomin Zhang & Peter Jonas, Parvalbumin+ interneurons obey unique connectivity rules and establish a powerful lateral-inhibition microcircuit in dentate gyrus. Nature Communications volume 9, Article number: 4605 (2018)
Parvalbumin cells (PV) cells are a type of inhibitory cell found all over the brain, and these neurons primarily use the inhibitory neurotransmitter GABA. Here the study focuses exclusively on what are the connections between PV cells and the excitatory granular cells(GC).They examined many different possible connections between PV and GC neurons. Using careful and tedious electrophysiological experiments they were able to reliably tell if two neurons were connected by either an inhibitory synapse, excitatory synapse, or gap junction. Specifically to do this, they would use whole cell patch clamp recording from 8 cells in the dentate gyrus at a time. They would use a voltage clamp to hold the membrane voltage constant and measure weather this cause a postsynaptic inhibitory current or excitatory current in the cells. Because there were 8 cells and 3 connection types there are 9098 different possible connections. These different connection possibilities are known as motifs and plotted the relative and absolute abundance of the motifs in figure 5 of their paper. Furthermore figure 5b compared the real network to simulated random networks. I have attached a screenshot of the figure below.
As many previous studies have shown, they did find that a single PV cells connects to many GC cells [motif 9], and that many different GC cells connect to a single PV cell [motif 7]. This means that a single PV cell activity can laterally inhibit many GC cells. This gives the PV cell a strong local inhibitory reach. Yet there study did not stop there, they also found that PV cells are highly locally connected with each other. PV cells form two types of connections with each others. First they commonly connected with gap junctions [motif 2] which are electrical synapses that share the cytoplasm between cells. This allows the electrical signals to diffuse between cells. Thus if one cell is spiking, the spikes can be recorded in the electrically coupled cells. However, PV cells also form recurrent inhibitory connections between each other. This means that cell 1 inhibits cell 2 and likewise cell 2 inhibits cell 1. Interestingly, this means that if cell 1 is spiking, cell 2 is off, and if cell 2 is spiking cell 1 is off. However to complicate things, Recurrent inhibition is often found with gap junctions, and gap junctions work in the opposite fashion, i.e cell 1 is spiking then cell 2 is also spiking and vise versa.
The fact that these networks contain both inhibition and gap junctions is key because other studies, including one from Zochowski et al. have shown that inhibitory networks with gap junctions can form synchronized activity across the network, or can for highly complex heterogeneous states, that can process asymmetries in inputs into the inhibitory network. Thus the presence of highly recurrent connections and gap junctions in PV cells, likely suggests that they are helpful in processing information on the microcircuit level.
 |
| Figure 5 from the paper. 5a shows the different motifs that they examined. The boxed motifs where statistically more likely compared to a simulated random network. Here the synapses are white triangles are excitatory, black circles are inhibitory, and a resistor symbol is gap junction. 5b shows the Absolute number of motifs, the relative number of motifs compared to the simulated network, and the statistical significance of the result. |
Author: Alexander White
Source: Claudia Espinoza, Segundo Jose Guzman, Xiaomin Zhang & Peter Jonas, Parvalbumin+ interneurons obey unique connectivity rules and establish a powerful lateral-inhibition microcircuit in dentate gyrus. Nature Communications volume 9, Article number: 4605 (2018)
留言
張貼留言