In the mammalian cerebral cortex, the diversity of interneuronal subtypes underlies a division of labor subserving distinct modes of inhibitory control1–7. A unique mode of inhibitory control may be provided by inhibitory neurons that specifically suppress the firing of other inhibitory neurons. Such disinhibition could lead to the selective amplification of local processing and serve the important computational functions of gating and gain modulation8,9. Although several interneuron populations are known to target other interneurons to varying degrees10–15, little is known about interneurons specializing in disinhibition and their in vivo function. Here we show that a class of interneurons that express vasoactive intestinal polypeptide (VIP) mediates disinhibitory control in multiple areas of neocortex and is recruited by reinforcement signals. By combining optogenetic activation with single cell recordings, we examined the functional role of VIP interneurons in awake mice, and investigated the underlying circuit mechanisms in vitro in auditory and medial prefrontal cortices. We identified a basic disinhibitory circuit module in which activation of VIP interneurons transiently suppresses primarily somatostatin- and a fraction of parvalbumin-expressing inhibitory interneurons that specialize in the control of the input and output of principal cells, respectively3,6,16,17. During the performance of an auditory discrimination task, reinforcement signals (reward and punishment) strongly and uniformly activated VIP neurons in auditory cortex, and in turn VIP recruitment increased the gain of a functional subpopulation of principal neurons. These results reveal a specific cell-type and microcircuit underlying disinhibitory control in cortex and demonstrate that it is activated under specific behavioural conditions.
Studies of long-term potentiation (LTP) and long-term depression (LTD) strongly suggest that individual synapses can be bidirectionally modified. A central question is the biochemical mechanisms that make LTP and LTD persistent. Previous theoretical models have proposed that the autophosphorylation properties of CaMKII could underlie a bistable molecular switch that maintains LTP and there is experimental support for this mechanism. In contrast, there has been comparatively little theoretical or experimental work regarding the mechanisms that maintain LTD. Several lines of evidence indicate that LTD is not simply a reversal of previous LTP, but rather involves separate biochemical reactions. These findings indicate that a minimal model of the synapse must involve a tristable system. Here we describe a phosphatase (PP2A) switch, which together with a kinase switch form a tristable system. PP2A can be activated by a Ca2+-dependent process, but can also be phosphorylated and inactivated by CaMKII. When dephosphorylated, PP2A can dephosphorylate itself. We show that these properties can lead to a persistent increase in PP2A during LTD (as reported experimentally), thus forming a phosphatase switch. We show that the coupled PP2A and CaMKII switches lead to a tristable system in which the kinase activity is high in the LTP state; the PP2A activity is high in the LTD state and neither activity is high in the basal state. Our results provide an explanation for the recent finding that inhibition of PP2A prevents LTD induction.
Ca 2ϩ /calmodulin-dependent kinase II (CaMKII) is a key mediator of long-term potentiation (LTP). Whereas acute intracellular injection of catalytically active
The N-Methyl-D-Aspartate Receptor (NMDAR) hypofunction model of schizophrenia is based on the ability of NMDAR antagonists to produce many symptoms of the disease. Recent work in rat shows that NMDAR antagonist works synergistically with dopamine to produce delta frequency bursting in the thalamus. This finding, together with other results in the literature, suggests a mechanism for the sudden onset of schizophrenia. Among the thalamic nuclei most activated by NMDAR antagonist is the nucleus reuniens. This nucleus excites the CA1 region of the hippocampus. Experiments indicate that such activation can lead to excitation of dopaminergic cells of the VTA by a polysynaptic pathway. The resulting elevation of dopamine in the thalamus will enhance thalamic bursting, thereby creating a loop with the potential for positive feedback. We show through computer simulations that, in individuals with susceptibility to schizophrenia (e.g., because of partially compromised NMDAR function), an event that stimulates the dopamine system, such as stress, can cause the system to reach the threshold for thalamic bursting. When this occurs, positive feedback in the loop will cause all components to become highly active and to remain active after the triggering stimulus is removed. This is a physiologically specific hypothesis for the sudden and lasting transition that underlies the psychotic break in schizophrenia. Furthermore, the model provides an explanation for the observed selective activation of the CA1 hippocampal region in schizophrenia. The model also predicts an increase of basal activity in the dopamine system and thalamus; the relevant evidence is reviewed.
CaMKII is an abundant synaptic protein strongly implicated in plasticity. Overexpression of autonomous (T286D) CaMKII in CA1 hippocampal cells enhances synaptic strength if T305/T306 sites are not phosphorylated, but decreases synaptic strength if they are phosphorylated. It has generally been thought that spine size and synaptic strength covary; however, the ability of CaMKII and its various phosphorylation states to control spine size has not been previously examined. Using a unique method that allows the effects of overexpressed protein to be monitored over time, we found that all autonomous forms of CaMKII increase spine size. Thus, for instance, the T286D/T305D/T306D form increases spine size but decreases synaptic strength. Further evidence for such dissociation is provided by experiments with the T286D form that has been made catalytically dead. This form fails to enhance synaptic strength but increases spine size, presumably by a structural process. Thus very different mechanisms govern how CaMKII affects spine structure and synaptic function. S tudies have shown that there are structural correlates of synaptic plasticity. Photolysis of caged glutamate at individual spines produces long-term potentiation (LTP) and is accompanied by a persistent increase in spine size (1, 2). Similarly, the induction of long-term depression (LTD) causes spine shrinkage (3). Moreover, the spines on a dendrite vary dramatically in size (4) in a manner that correlates with the postsynaptic strength of the synapse on that spine (5, 6).CaMKII is one of the most abundant proteins in the brain (7). It is activated during LTP (8, 9), an activation that is required for potentiation (10-12). This activation is dependent on phosphorylation at T286, which makes the enzyme autonomous of Ca 2+ /calmodulin (13). The instructive role of CaMKII in the control of synaptic strength has been examined by overexpression of various phosphorylation states of the kinase. Recent work (14) revealed that the effect of the autonomous form (T286D) has unexpected complexity that depends on additional phosphorylation sites (T305/T306). These sites have been previously implicated in metaplasticity (15). If these sites are not phosphorylated (T286D/T305A/T306A), potentiation is produced that occludes LTP (14). However, if the sites are pseudophosphorylated (T286D/T305D/T305D), depression is produced that occludes LTD (14). Given the correlation of synaptic strength and spine size noted above, we expected that the forms of CaMKII that increase synaptic strength would increase spine size, whereas those that decrease synaptic strength would decrease spine size. We tested this prediction and found that it is not correct. Autonomous CaMKII forms increase spine size regardless of whether synaptic strength is increased or decreased. The mechanisms by which CaMKII affects spine structure and synaptic strength thus have a different dependence on the phosphorylation state of the enzyme. This difference is underscored by a further finding: that a T286D form with an ...
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