Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of mo... more Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability.
In sensory systems, it is usually considered that mesopontine cholinergic neurons exert their mod... more In sensory systems, it is usually considered that mesopontine cholinergic neurons exert their modulatory action in the thalamus by enhancing the relay of sensory messages during states of neural network desynchronization. Here, we report a projection heretofore unknown of these cholinergic cells to the interpolar division of the brainstem trigeminal complex in rats. After FluoroGold injection in the interpolar nucleus, a number of retrogradely labeled cells were found bilaterally in the pedunculopontine tegmental nucleus, and immunostaining revealed that the vast majority of these cells were also positive for choline acetyltransferase. Immunostaining for the acetylcholine vesicular transporter confirmed the presence of cholinergic terminals in the interpolar nucleus, where electron microscopy showed that they make symmetric and asymmetric synaptic contacts with dendrites and axon terminals. In agreement with these anatomical data, recordings in slices showed that the cholinergic agonist carbachol depolarizes large-sized interpolaris cells and increases their excitability. Local application of carbachol in vivo enhances responses to adjacent whiskers, whereas systemic administration of the cholinergic antagonist scopolamine produces an opposite effect. Together, these results show that mesopontine cholinergic neurons exert a direct, effective control over receptive field size at the very first relay stations of the vibrissal system in rodents. As far as receptive field synthesis in the lemniscal pathway relies on intersubnuclear projections from the spinal complex, it follows that cholinergic modulation of sensory transmission in the interpolar nucleus will have a direct bearing on the type of messages that is forwarded to the thalamus and cerebral cortex.
A sample of 84 neurons in lamina VIa of rat somatosensory cortex (S1) was juxtacellularly labeled... more A sample of 84 neurons in lamina VIa of rat somatosensory cortex (S1) was juxtacellularly labeled with biocytin, and the axons of the neurons were traced. Three classes of cells were identified as corticothalamic, corticocortical, and local circuit neurons. Corticothalamic cells (46%) are small, short pyramids projecting either to the ventral posteromedial nucleus alone or to the posterior group as
Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of mo... more Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability.
In sensory systems, it is usually considered that mesopontine cholinergic neurons exert their mod... more In sensory systems, it is usually considered that mesopontine cholinergic neurons exert their modulatory action in the thalamus by enhancing the relay of sensory messages during states of neural network desynchronization. Here, we report a projection heretofore unknown of these cholinergic cells to the interpolar division of the brainstem trigeminal complex in rats. After FluoroGold injection in the interpolar nucleus, a number of retrogradely labeled cells were found bilaterally in the pedunculopontine tegmental nucleus, and immunostaining revealed that the vast majority of these cells were also positive for choline acetyltransferase. Immunostaining for the acetylcholine vesicular transporter confirmed the presence of cholinergic terminals in the interpolar nucleus, where electron microscopy showed that they make symmetric and asymmetric synaptic contacts with dendrites and axon terminals. In agreement with these anatomical data, recordings in slices showed that the cholinergic agonist carbachol depolarizes large-sized interpolaris cells and increases their excitability. Local application of carbachol in vivo enhances responses to adjacent whiskers, whereas systemic administration of the cholinergic antagonist scopolamine produces an opposite effect. Together, these results show that mesopontine cholinergic neurons exert a direct, effective control over receptive field size at the very first relay stations of the vibrissal system in rodents. As far as receptive field synthesis in the lemniscal pathway relies on intersubnuclear projections from the spinal complex, it follows that cholinergic modulation of sensory transmission in the interpolar nucleus will have a direct bearing on the type of messages that is forwarded to the thalamus and cerebral cortex.
A sample of 84 neurons in lamina VIa of rat somatosensory cortex (S1) was juxtacellularly labeled... more A sample of 84 neurons in lamina VIa of rat somatosensory cortex (S1) was juxtacellularly labeled with biocytin, and the axons of the neurons were traced. Three classes of cells were identified as corticothalamic, corticocortical, and local circuit neurons. Corticothalamic cells (46%) are small, short pyramids projecting either to the ventral posteromedial nucleus alone or to the posterior group as
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Papers by Zhong-wei Zhang