Summary: Researchers report the intrinsic excitability of neurons in response to immune cell reaction to bacteria depends on the different neuron subtypes in rats.
Source: Kyoto University
A new study reports that immune cell responses to bacteria affect the intrinsic excitability of rat neuronal subtypes differently.
The findings have implications for neural network control, including irregularities that lead to neurological and psychiatric disorders.
If a neuron can be viewed as a battery that stores and discharges electricity, then its intrinsic excitability can be viewed as the battery’s storage capacity. While higher energy storage is usually viewed positively, overcharging a battery could cause it to overheat and become damaged.
Like all immune cells, microglia serve to kill off pathogens and infections, and their activity is known to regulate the intrinsic excitability of neurons. Yet, when microglia are over-stimulated, they can cause inflammation, pain, and other ailments.
“For example, unmanaged intrinsic excitability has been attributed to psychiatric diseases, like mood disorders,” explains author Gen Ohtsuki of Kyoto University.
Current knowledge on neuronal regulation comes from experiments analyzing Purkinje cells. These neurons are found in the cerebellum, which is considered an evolutionarily ancient part of the brain and responsible for motor control.
Less understood are the effects on the intrinsic excitability of pyramidal cells, which are neurons found in the cortex: the part of the brain associated with higher-level thinking.
The team observed that calcium-activated SK ion channels in pyramidal cells were modulated by microglia, which is the same for Purkinje cells. However, in pyramidal cells, SK channels were upregulated, while they were downregulated in Purkinje cells.
“The effects were completely opposite,” notes Ohtsuki.
The pyramidal cells appeared to react to the same cytokine — TNFa or tumor necrosis factor alpha — secreted by activated microglia: one of the most common cytokines released by immune cells in response to an infection.
However, the difference in SK channel regulation resulted in lower intrinsic excitability of pyramidal cells but higher intrinsic excitability of Purkinje cells. These inverted responses or directionalities to the same input are not uncommon between Purkinje and pyramidal cells and have also been seen with synaptic plasticity.
Ohtsuki cautions that: “The effects of microglia in one part of the brain should not be generalized to the entire organ. Our findings show that we need to study different brain regions separately to understand how microglia regulate neuronal function and how immunity impairs plasticity of neurons in psychiatric-diseased brains.”
Lipopolysaccharide (LPS), an outer component of Gram-negative bacteria, induces a strong response of innate immunity via microglia, which triggers a modulation of the intrinsic excitability of neurons. However, it is unclear whether the modulation of neurophysiological properties is similar among neurons.
Here, we found the hypoexcitability of layer 5 (L5) pyramidal neurons after exposure to LPS in the medial prefrontal cortex (mPFC) of juvenile rats.
We recorded the firing frequency of L5 pyramidal neurons long-lastingly under in vitro whole-cell patch-clamp, and we found a reduction of the firing frequency after applying LPS.
A decrease in the intrinsic excitability against LPS-exposure was also found in L2/3 pyramidal neurons but not in fast-spiking interneurons. The decrease in the excitability by immune-activation was underlain by increased activity of small-conductance Ca2+-activated K+ channels (SK channels) in the pyramidal neurons and tumor necrosis factor (TNF)-α released from microglia.
We revealed that the reduction of the firing frequency of L5 pyramidal neurons was dependent on intraneuronal Ca2+ and PP2B.
These results suggest the hypoexcitability of pyramidal neurons caused by the upregulation of SK channels via Ca2+-dependent phosphatase during acute inflammation in the mPFC. Such a mechanism is in contrast to that of cerebellar Purkinje cells, in which immune activation induces hyperexcitability via downregulation of SK channels.
Further, a decrease in the frequency of spontaneous inhibitory synaptic transmission reflected network hypoactivity.
Therefore, our results suggest that the directionality of the intrinsic plasticity by microglia is not consistent, depending on the brain region and the cell type.