25 research outputs found
A Presynaptic Kainate Receptor Is Involved in Regulating the Dynamic Properties of Thalamocortical Synapses during Development
AbstractPrevious studies have shown that pharmacological activation of presynaptic kainate receptors at glutamatergic synapses facilitates or depresses transmission in a dose-dependent manner. However, the only synaptically activated kainate autoreceptor described to date is facilitatory. Here, we describe a kainate autoreceptor that depresses synaptic transmission. This autoreceptor is present at developing thalamocortical synapses in the barrel cortex, specifically regulates transmission at frequencies corresponding to those observed in vivo during whisker activation, and is developmentally down regulated during the first postnatal week. This receptor may, therefore, limit the transfer of high-frequency activity to the developing cortex, the loss of which mechanism may be important for the maturation of sensory processing
A Distinct Class of Slow ( approximately 0.2-2 Hz) Intrinsically Bursting Layer 5 Pyramidal Neurons Determines UP/DOWN State Dynamics in the Neocortex
During sleep and anesthesia, neocortical neurons exhibit rhythmic UP/DOWN membrane potential states. Although UP states are maintained by synaptic activity, the mechanisms that underlie the initiation and robust rhythmicity of UP states are unknown. Using a physiologically validated model of UP/DOWN state generation in mouse neocortical slices whereby the cholinergic tone present in vivo is reinstated, we show that the regular initiation of UP states is driven by an electrophysiologically distinct subset of morphologically identified layer 5 neurons, which exhibit intrinsic rhythmic low-frequency burst firing at approximately 0.2-2 Hz. This low-frequency bursting is resistant to block of glutamatergic and GABAergic transmission but is absent when slices are maintained in a low Ca(2+) medium (an alternative, widely used model of cortical UP/DOWN states), thus explaining the lack of rhythmic UP states and abnormally prolonged DOWN states in this condition. We also characterized the activity of various other pyramidal and nonpyramidal neurons during UP/DOWN states and found that an electrophysiologically distinct subset of layer 5 regular spiking pyramidal neurons fires earlier during the onset of network oscillations compared with all other types of neurons recorded. This study, therefore, identifies an important role for cell-type-specific neuronal activity in driving neocortical UP states
Rapid and Differential Regulation of AMPA and Kainate Receptors at Hippocampal Mossy Fibre Synapses by PICK1 and GRIP
AbstractWe identified four PDZ domain-containing proteins, syntenin, PICK1, GRIP, and PSD95, as interactors with the kainate receptor (KAR) subunits GluR52b, GluR52c, and GluR6. Of these, we show that both GRIP and PICK1 interactions are required to maintain KAR-mediated synaptic function at mossy fiber-CA3 synapses. In addition, PKCα can phosphorylate ct-GluR52b at residues S880 and S886, and PKC activity is required to maintain KAR-mediated synaptic responses. We propose that PICK1 targets PKCα to phosphorylate KARs, causing their stabilization at the synapse by an interaction with GRIP. Importantly, this mechanism is not involved in the constitutive recycling of AMPA receptors since blockade of PDZ interactions can simultaneously increase AMPAR- and decrease KAR-mediated synaptic transmission at the same population of synapses
Developmental and Activity Dependent Regulation of Ionotropic Glutamate Receptors at Synapses
Glutamate receptors mediate the majority of excitatory responses in the central nervous system. The establishment and refinement of glutamatergic synaptic connections depend on the concerted actions of a-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), and kainate (KA) type ionotropic glutamate receptors (iGluRs) and G-protein coupled metabotropic receptors. While a lot remains to be clarified, the most is known about the mechanisms by which the iGluR subtypes are targeted and how this is influenced by synaptic activity on both short and long time scales. Changes in their subunit compositions are also input specific and developmentally regulated. The identification of key molecular components of the postsynaptic density (PSD) and novel proteins that influence receptor targeting and clustering have started to reveal the underlying molecular mechanisms of the trafficking and targeting of iGluRs. Here we discuss the evidence that these basic mechanisms are used during developmental synaptic plasticity
Coordinated Acetylcholine Release in Prefrontal Cortex and Hippocampus Is Associated with Arousal and Reward on Distinct Timescales.
Cholinergic neurotransmission throughout the
neocortex and hippocampus regulates arousal,
learning, and attention. However, owing to the poorly
characterized timing and location of acetylcholine
release, its detailed behavioral functions remain unclear.
Using electrochemical biosensors chronically
implanted in mice, we made continuous measurements
of the spatiotemporal dynamics of acetylcholine
release across multiple behavioral states.
We found that tonic levels of acetylcholine release
were coordinated between the prefrontal cortex
and hippocampus and maximal during training on a
rewarded working memory task. Tonic release also
increased during REM sleep but was contingent on
subsequent wakefulness. In contrast, coordinated
phasic acetylcholine release occurred only during
the memory task and was strongly localized to
reward delivery areas without being contingent on
trial outcome. These results show that coordinated
acetylcholine release between the prefrontal cortex
and hippocampus is associated with reward and
arousal on distinct timescales, providing dual mechanisms
to support learned behavior acquisition during
cognitive task performance
Coordinated Acetylcholine Release in Prefrontal Cortex and Hippocampus Is Associated with Arousal and Reward on Distinct Timescales.
Cholinergic neurotransmission throughout the
neocortex and hippocampus regulates arousal,
learning, and attention. However, owing to the poorly
characterized timing and location of acetylcholine
release, its detailed behavioral functions remain unclear.
Using electrochemical biosensors chronically
implanted in mice, we made continuous measurements
of the spatiotemporal dynamics of acetylcholine
release across multiple behavioral states.
We found that tonic levels of acetylcholine release
were coordinated between the prefrontal cortex
and hippocampus and maximal during training on a
rewarded working memory task. Tonic release also
increased during REM sleep but was contingent on
subsequent wakefulness. In contrast, coordinated
phasic acetylcholine release occurred only during
the memory task and was strongly localized to
reward delivery areas without being contingent on
trial outcome. These results show that coordinated
acetylcholine release between the prefrontal cortex
and hippocampus is associated with reward and
arousal on distinct timescales, providing dual mechanisms
to support learned behavior acquisition during
cognitive task performance
Thalamocortical input onto layer 5 pyramidal neurons measured using quantitative large-scale array tomography
The subcellular locations of synapses on pyramidal neurons strongly influences dendritic integration and synaptic plasticity. Despite this, there is little quantitative data on spatial distributions of specific types of synaptic input. Here we use array tomography (AT), a high-resolution optical microscopy method, to examine thalamocortical (TC) input onto layer 5 pyramidal neurons. We first verified the ability of AT to identify synapses using parallel electron microscopic analysis of TC synapses in layer 4. We then use large-scale AT to measure TC synapse distribution on L5 pyramdial neurons in a 1.00 x 0.83 x 0.21 mm^3 volume of mouse somatosensory cortex. We found that TC synapses primarily target basal dendrites in layer 5, but also make a considerable input to proximal apical dendrites in L4, consistent with previous work. Our analysis further suggests that TC inputs are biased towards certain branches and, within branches, synapses show significant clustering with an excess of TC synapse nearest neighbors within 5-15 ÎĽm compared to a random distribution. Thus, we show that AT is a sensitive and quantitative method to map specific types of synaptic input on the dendrites of entire neurons. We anticipate that this technique will be of wide utility for mapping functionally-relevant anatomical connectivity in neural circuits