Dysfunction of Cortical Dendritic Integration in Neuropathic Pain Reversed by Serotoninergic Neuromodulation

Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target

Astrocyte function from information processing to cognition and cognitive impairment

Astrocytes serve important roles that affect recruitment and function of neurons at the local and network levels. Here we review the contributions of astrocyte signaling to synaptic plasticity, neuronal network oscillations, and memory function. The roles played by astrocytes are not fully understood, but astrocytes seem to contribute to memory consolidation and seem to mediate the effects of vigilance and arousal on memory performance. Understanding the role of astrocytes in cognitive processes may also advance our understanding of how these processes go awry in pathological conditions. Indeed, abnormal astrocytic signaling can cause or contribute to synaptic and network imbalances, leading to cognitive impairment. We discuss evidence for this from animal models of Alzheimer's disease and multiple sclerosis and from animal studies of sleep deprivation and drug abuse and addiction. Understanding the emerging roles of astrocytes in cognitive function and dysfunction will open up a large array of new therapeutic opportunities

Diving into new depths of astrocyte signaling

Astrocytes are crucial contributors to brain homeostasis. Yet the lack of ad hoc analysis tools has prevented indepth characterization of astrocyte-derived signals. In a new study, the authors present an image-analysis toolbox that captures the complexity of astrocyte activity and enables our understanding of astrocytic physiology

Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine

Astrocytes are essential contributors to neuronal function. As a consequence, disturbed astrocyte-neuron interactions are involved in the pathophysiology of several neurological disorders, with a strong impact on brain circuits and behavior. Here, we describe altered cortical physiology in a genetic mouse model of familial hemiplegic migraine type 2 (FHM2), with reduced expression of astrocytic Na$^{+}$,K$^{+}$-ATPases. We used whole-cell electrophysiology, two-photon microscopy, and astrocyte gene rescue to demonstrate that an impairment in astrocytic glutamate uptake promotes NMDA spike generation in dendrites of cingulate cortex pyramidal neurons and enhances output firing of these neurons. Astrocyte compensation of the defective ATPase in the cingulate cortex rescued glutamate uptake, prevented abnormal NMDA spikes, and reduced sensitivity to cranial pain triggers. Together, our results demonstrate that impaired astrocyte function alters neuronal activity in the cingulate cortex and facilitates migraine-like cranial pain states in a mouse model of migraine

Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine

Astrocytes are essential contributors to neuronal function. As a consequence, disturbed astrocyte-neuron interactions are involved in the pathophysiology of several neurological disorders, with a strong impact on brain circuits and behavior. Here, we describe altered cortical physiology in a genetic mouse model of familial hemiplegic migraine type 2 (FHM2), with reduced expression of astrocytic Na+,K+-ATPases. We used whole-cell electrophysiology, two-photon microscopy, and astrocyte gene rescue to demonstrate that an impairment in astrocytic glutamate uptake promotes NMDA spike generation in dendrites of cingulate cortex pyramidal neurons and enhances output firing of these neurons. Astrocyte compensation of the defective ATPase in the cingulate cortex rescued glutamate uptake, prevented abnormal NMDA spikes, and reduced sensitivity to cranial pain triggers. Together, our results demonstrate that impaired astrocyte function alters neuronal activity in the cingulate cortex and facilitates migraine-like cranial pain states in a mouse model of migraine.ISSN:2375-254

Differences in glutamate uptake between cortical regions impact neuronal NMDA receptor activation

Removal of synaptically-released glutamate by astrocytes is necessary to spatially and temporally limit neuronal activation. Recent evidence suggests that astrocytes may have specialized functions in specific circuits, but the extent and significance of such specialization are unclear. By performing direct patch-clamp recordings and two-photon glutamate imaging, we report that in the somatosensory cortex, glutamate uptake by astrocytes is slower during sustained synaptic stimulation when compared to lower stimulation frequencies. Conversely, glutamate uptake capacity is increased in the frontal cortex during higher frequency synaptic stimulation, thereby limiting extracellular buildup of glutamate and NMDA receptor activation in layer 5 pyramidal neurons. This efficient glutamate clearance relies on Na/K-ATPase function and both GLT-1 and non-GLT-1 transporters. Thus, by enhancing their glutamate uptake capacity, astrocytes in the frontal cortex may prevent excessive neuronal excitation during intense synaptic activity. These results may explain why diseases associated with network hyperexcitability differentially affect individual brain areas

Differences in glutamate uptake between cortical regions impact neuronal NMDA receptor activation

Removal of synaptically-released glutamate by astrocytes is necessary to spatially and temporally limit neuronal activation. Recent evidence suggests that astrocytes may have specialized functions in specific circuits, but the extent and significance of such specialization are unclear. By performing direct patch-clamp recordings and two-photon glutamate imaging, we report that in the somatosensory cortex, glutamate uptake by astrocytes is slower during sustained synaptic stimulation when compared to lower stimulation frequencies. Conversely, glutamate uptake capacity is increased in the frontal cortex during higher frequency synaptic stimulation, thereby limiting extracellular buildup of glutamate and NMDA receptor activation in layer 5 pyramidal neurons. This efficient glutamate clearance relies on Na+/K+-ATPase function and both GLT-1 and non-GLT-1 transporters. Thus, by enhancing their glutamate uptake capacity, astrocytes in the frontal cortex may prevent excessive neuronal excitation during intense synaptic activity. These results may explain why diseases associated with network hyperexcitability differentially affect individual brain areas.ISSN:2399-364