No abstract

A full list of affiliations appears at the end of the paper. 'N euroglia' or 'glia' are collective terms describing cells of neuroepithelial (oligodendrocytes, astrocytes, oligodendrocyte progenitor cells, ependymal cells), neural crest (peripheral glia), and myeloid (microglia) origin. Changes in neuroglia associated with diseases of the CNS have been noted, characterized, and conceptualized from the very dawn of neuroglial research. Rudolf Virchow, in a lecture to students and medical doctors in 1858, stressed that 'this very interstitial tissue [that is, neuroglia] of the brain and spinal marrow is one of the most frequent seats of morbid change... ' 1. Changes in the shape, size, or number of glial cells in various pathological contexts have been frequently described by prominent neuroanatomists 2. In particular, hypertrophy of astrocytes was recognized very early as an almost universal sign of CNS pathology: 'the protoplasmic glia elements [that is, astrocytes] are really the elements which exhibit a morbid hypertrophy in pathological conditions' 3. Neuroglial proliferation was thought to accompany CNS lesions, leading to early suggestions that proliferating glia fully replaced damaged neuronal elements 4. Thus, a historical consensus was formed that a change in 'the appearance of neuroglia serves as a delicate indicator of the action of noxious influences upon the central nervous system, ' and the concept of 'reactionary change or gliosis' was accepted 5. While the origin of 'gliosis' is unclear (glia + osis in Greek means 'glial condition or process'; in Latin the suffix-osis acquired the additional meaning of 'disease'; hence 'astrogliosis'

Astrocytes play active roles in brain physiology. They respond to neurotransmitters and modulate neuronal excitability and synaptic function. However, the influence of astrocytes on synaptic transmission and plasticity at the single synapse level is unknown. Ca(2+) elevation in astrocytes transiently increased the probability of transmitter release at hippocampal area CA3-CA1 synapses, without affecting the amplitude of synaptic events. This form of short-term plasticity was due to the release of glutamate from astrocytes, a process that depended on Ca(2+) and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein and that activated metabotropic glutamate receptors (mGluRs). The transient potentiation of transmitter release became persistent when the astrocytic signal was temporally coincident with postsynaptic depolarization. This persistent plasticity was mGluR-mediated but N-methyl-d-aspartate receptor-independent. These results indicate that astrocytes are actively involved in the transfer and storage of synaptic information.

The synaptic control of the astrocytic intracellular Ca 2ϩ is crucial in the reciprocal astrocyte-neuron communication. Using electrophysiological and Ca 2ϩ imaging techniques in rat hippocampal slices, we investigated the astrocytic Ca 2ϩ signal modulation induced by synaptic terminals that use glutamate and acetylcholine. Ca 2ϩ elevations were evoked by glutamate released from Schaffer collaterals and by acetylcholine, but not glutamate, released by alveus stimulation, indicating that astrocytes discriminate the activity of different synapses belonging to different axon pathways. The Ca 2ϩ signal was modulated bidirectionally by simultaneous activation of both pathways, being depressed at high stimulation frequencies and enhanced at low frequencies. The Ca 2ϩ modulation was attributable to astrocytic intrinsic properties, occurred at discrete regions of the processes, and controlled the intracellular expansion of the Ca 2ϩ signal. In turn, astrocyte Ca 2ϩ signal elicited NMDA receptor-mediated currents in pyramidal neurons. Therefore, because astrocytes discriminate and integrate synaptic information, we propose that they can be considered as cellular elements involved in the information processing by the nervous system.

In vivo and in vitro studies reveal that astrocytes, classically considered supportive cells for neurons, regulate synaptic plasticity in the mouse hippocampus and are directly involved in information storage.

Cell type–specific glial networks Glial cells respond to neurotransmitters when nerve cells communicate with each other. Glial cells themselves release gliotransmitters that regulate neural synaptic transmission. Martín et al. studied this reciprocal relationship in a brain region called the dorsal striatum, which has two types of experimentally identifiable neurons and two types of synapses (see the Perspective by Gittis and Brasier). Subpopulations of glial cells selectively responded to the activity of one specific type of neuron. In turn, these specifically activated glial cells signaled only to the same type of neurons but not the other, indicating that glial-nerve signaling is largely cell-type specific. Science , this issue p. 730 ; see also p. 690

Astrocytes play important roles in synaptic transmission and plasticity. Despite in vitro evidence, their causal contribution to cortical network activity and sensory information processing in vivo remains unresolved. Here we report that selective photostimulation of astrocytes with channelrhodopsin-2 in primary visual cortex enhances both excitatory and inhibitory synaptic transmission, through the activation of type 1a metabotropic glutamate receptors. Photostimulation of astrocytes in vivo increases the spontaneous firing of parvalbumin-positive (PV+) inhibitory neurons, while excitatory and somatostatin-positive (SOM+) neurons show either an increase or decrease in their activity. Moreover, PV+ neurons show increased baseline visual responses and reduced orientation selectivity to visual stimuli, whereas excitatory and SOM+ neurons show either increased or decreased baseline visual responses together with complementary changes in orientation selectivity. Therefore, astrocyte activation, through the dual control of excitatory and inhibitory drive, influences neuronal integrative features critical for sensory information processing.

Although cholinergic innervation of the cortex by the nucleus basalis (NB) is known to modulate cortical neuronal responses and instruct cortical plasticity, little is known about the underlying cellular mechanisms. Using cell-attached recordings in vivo, we demonstrate that electrical stimulation of the NB, paired with visual stimulation, can induce significant potentiation of visual responses in excitatory neurons of the primary visual cortex in mice. We further show with in vivo two-photon calcium imaging, ex vivo calcium imaging, and whole-cell recordings that this pairing-induced potentiation is mediated by direct cholinergic activation of primary visual cortex astrocytes via muscarinic AChRs. The potentiation is absent in conditional inositol 1,4,5 trisphosphate receptor type 2 KO mice, which lack astrocyte calcium activation, and is stimulus-specific, because pairing NB stimulation with a specific visual orientation reveals a highly selective potentiation of responses to the paired orientation compared with unpaired orientations. Collectively, these findings reveal a unique and surprising role for astrocytes in NB-induced stimulusspecific plasticity in the cerebral cortex.acetylcholine | response potentiation | glial calcium | basal forebrain | astrocyte-neuron interactions S ensory experience associated with nucleus basalis (NB)-driven, cholinergic activation of the cortex (1) has been shown to induce cortical plasticity at both single-cell and cortical map levels (2-6). To understand how cortical responses and representations can be altered by experience during cholinergic modulation, it is critical to identify the circuit elements involved and define how their interactions can contribute to the restructuring of cortical network dynamics.Previous studies have shown that multiple cortical cell types, including neurons (7-9) and astrocytes (10-12), can be responsive to ACh. Among these cell types, astrocytes are a promising candidate for contributing to NB-mediated cortical plasticity. Ex vivo studies have implicated hippocampal astrocytes in synaptic potentiation [(13-15) compare with (16)], demonstrating that they can potentially provide a powerful means of altering the state of neuronal networks to induce plasticity. More recently, studies using combined somatosensory and cholinergic stimulation have revealed that NB-induced astrocytic activation can induce potentiation of local field potentials recorded in somatosensory cortex (17,18). These findings open up several key questions. Does the NB-mediated potentiation manifest at the level of single neurons and astrocytes? If so, does the potentiation influence specific features of single neuronal responses and representations? In particular, is the potentiation a nonspecific increase in responses independent of sensory stimulus features, or does it selectively facilitate responses to stimuli that have been paired with NB stimulation?The primary visual cortex (V1) provides an excellent model system to address these issues. Modulation by ACh in general an...