AMPA receptor regulation during synaptic plasticity in hippocampus and neocortex

Discovery of long-term potentiation (LTP) in the dentate gyrus of the rabbit hippocampus by Bliss and L?mo opened up a whole new field to study activity-dependent long-term synaptic modifications in the brain. Since then hippocampal synapses have been a key model system to study the mechanisms of different forms of synaptic plasticity. At least for the postsynaptic forms of LTP and long-term depression (LTD), regulation of AMPA receptors (AMPARs) has emerged as a key mechanism. While many of the synaptic plasticity mechanisms uncovered in at the hippocampal synapses apply to synapses across diverse brain regions, there are differences in the mechanisms that often reveal the specific functional requirements of the brain area under study. Here we will review AMPAR regulation underlying synaptic plasticity in hippocampus and neocortex. The main focus of this review will be placed on postsynaptic forms of synaptic plasticity that impinge on the regulation of AMPARs using hippocampal CA1 and primary sensory cortices as examples. And through the comparison, we will highlight the key similarities and functional differences between the two synapses.     

Unified postsynaptic mechanism of plasticity in the striatum, neocortex, hippocampus, and cerebellum

The unitary postsynaptic mechanism of plasticity in striatum, neocortex, hippocampus and cerebellum involves the LTP/LTD excitation as result of AMPA and NMDA receptor phosphorylation/dephosphorylation, while the LTP/LTD of inhibition is the result of the GABA receptor phosphorylation/dephosphorylation. It follows from this mechanism that when NMDA channels are closed, the determinant role in receptor phosphorylation is played by the PKG. When the NMDA channels are open, the determinant role in receptor phosphorylation is played by the PKC and CaMKII.     

Cannabinoid receptors contribute to astroglial Ca2+-signalling and control of synaptic plasticity in the neocortex

Communication between neuronal and glial cells is thought to be very important for many brain functions. Acting via release of gliotransmitters, astrocytes can modulate synaptic strength. The mechanisms underlying ATP release from astrocytes remain uncertain with exocytosis being the most intriguing and debated pathway. We have demonstrated that ATP and d-serine can be released from cortical astrocytes in situ by a SNARE-complex-dependent mechanism. Exocytosis of ATP from astrocytes can activate post-synaptic P2X receptors in the adjacent neurons, causing a downregulation of synaptic and extrasynaptic GABA receptors in cortical pyramidal neurons. We showed that release of gliotransmitters is important for the NMDA receptor-dependent synaptic plasticity in the neocortex. Firstly, induction of long-term potentiation (LTP) by five episodes of theta-burst stimulation (TBS) was impaired in the neocortex of dominant-negative (dn)-SNARE mice. The LTP was rescued in the dn-SNARE mice by application of exogenous non-hydrolysable ATP analogues. Secondly, we observed that weak sub-threshold stimulation (two TBS episodes) became able to induce LTP when astrocytes were additionally activated via CB-1 receptors. This facilitation was dependent on activity of ATP receptors and was abolished in the dn-SNARE mice. Our results strongly support the physiological relevance of glial exocytosis for glia–neuron communications and brain function.     

Interneurons in the developing human neocortex

Cortical interneurons play a crucial role in the functioning of cortical microcircuitry as they provide inhibitory input to projection (pyramidal) neurons. Despite their involvement in various neurological and psychiatric disorders, our knowledge about their development in human cerebral cortex is still incomplete. Here we demonstrate that at the beginning of corticogenesis, at embryonic 5 gestation weeks (gw, Carnegie stage 16) in human, early neurons could be labeled with calretinin, calbindin, and GABA antibodies. These immunolabeled cells show a gradient from the ganglionic eminences (GE) toward the neocortex, suggesting that GE is a well conserved source of early born cortical interneurons from rodents to human. At mid-term (20 gw), however, a subset of calretinin(+) cells proliferates in the cortical subventricular zone (SVZ), suggesting a second set of interneuron progenitors that have neocortical origin. Neuropeptide Y, somatostatin, or parvalbumin cells are sparse in mid-term cerebral cortex. In addition to the early source of cortical interneurons in the GE and later in the neocortical SVZ, other regions, such as the subpial granular layer, may also contribute to the population of human cortical interneurons. In conclusion, our findings from cryosections and previous in vitro results suggest that cortical interneuron progenitor population is more complex in humans relative to rodents. The increased complexity of progenitors is probably evolutionary adaptation necessary for development of the higher brain functions characteristic to humans.     

Spiral wave dynamics in neocortex

Although spiral waves are ubiquitous features of nature and have been observed in many biological systems, their existence and potential function in mammalian cerebral cortex remain uncertain. Using voltage-sensitive dye imaging, we found that spiral waves occur frequently in the neocortex in?vivo, both during pharmacologically induced oscillations and during sleep-like states. While their life span is limited, spiral waves can modify ongoing cortical activity by influencing oscillation frequencies and spatial coherence and by reducing amplitude in the area surrounding the spiral phase singularity. During sleep-like states, the rate of occurrence of spiral waves varies greatly depending on brain states. These results support the hypothesis that spiral waves, as an emergent activity pattern, can organize and modulate cortical population activity on the mesoscopic scale and may contribute to both normal cortical processing and to pathological patterns of activity such as those found in epilepsy.     

Dense inhibitory connectivity in neocortex

The connectivity diagram of neocortical circuits is still unknown, and there are conflicting data as to whether cortical neurons are wired specifically or not. To investigate the basic structure of cortical microcircuits, we use a two-photon photostimulation technique that enables the systematic mapping of synaptic connections with single-cell resolution. We map the inhibitory connectivity between upper layers somatostatin-positive GABAergic interneurons and pyramidal cells in mouse frontal cortex. Most, and sometimes all, inhibitory neurons are locally connected to every sampled pyramidal cell. This dense inhibitory connectivity is found at both young and mature developmental ages. Inhibitory innervation of neighboring pyramidal cells is similar, regardless of whether they are connected among themselves or not. We conclude that local inhibitory connectivity is promiscuous, does not form subnetworks, and can approach the theoretical limit of a completely connected synaptic matrix.     

Choline acetyltransferase-containing neurons in the human parietal neocortex

A number of immunocytochemical studies have indicated the presence of cholinergic neurons in the cerebral cortex of various species of mammals. Whether such cholinergic neurons in the human cerebral cortex are exclusively of subcortical origin is still debated. In this immunocytochemical study, the existence of cortical cholinergic neurons was investigated on surgical samples of human parietal association neocortex using a highly specific monoclonal antibody against choline acetyltransferase (ChAT), the acetylcholine biosynthesising enzyme. ChAT immunoreactivity was detected in a subpopulation of neurons located in layers II and III. These were small or medium-sized pyramidal neurons which showed cytoplasmic immunoreactivity in the perikarya and processes, often in close association to blood microvessels. This study, providing demonstration of ChAT neurons in the human parietal neocortex, strongly supports the existence of intrinsic cholinergic innervation of the human neocortex. It is likely that these neurons contribute to the cholinergic innervation of the intracortical microvessels.     

Ischemic and hypoxic depolarization in the rat neocortex

Cortical negative DC potential shifts were studied on two experimental models: focal cortical ischemia provoked by a photothrombotic occlusion of the distal part of the middle cerebral artery (dMCA) and a combination of systemic hypoxia induced by bilateral ligation of the common carotid arteries (temporary ligation of the left artery and permanent ligation of the right one) with breathing with 0.5% carbon monoxide (CO). The perifocal ischemic depolarization (ID) after the dMCA thrombosis was found to reach 28-33 mV and then gradually decline during 80 min to a certain residual level about 5 mV. Spontaneous depolarization didn't occur during hypoxia but it was easily provoked in one or both hemispheres by the waves of the cortical spreading depression (SD). The amplitude of hypoxic depolarization (HD) didn't exceed 20 mV, was remarkably stable during hypoxic condition (more than 60 min) and returned to the baseline level within 20-30 min after the cessation of CO breathing and releasing of the left carotid artery. Despite the similar durations of the ID and HD, their functional consequences differed greatly. The ID led to a damage of the nervous tissue as evidenced by a reduction of the SD amplitude (to 20-25%) and biphasic change in persistent negative potential (PNP) evoked by the SD wave alone. The 1.5-2-fold increase in the PNP amplitude in the perifocal region was the most prominent outcome of the ID. In contrast to the ID, the SD and PNP characteristics were unchanged after the HD. Such a discrepancy between the ID and HD can be related with their different origin. The results suggest that the HD is produced by blood-brain barrier processes associated with the intensive vasospasm and vasogenic edema. Besides these phenomena, the other well-known factors such as a disturbance of permeability of neuronal membranes, glutamatemediated exitotoxicity, and tissue destruction determine the ID noxious influences.