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1.
Nature ; 624(7991): 415-424, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38092908

ABSTRACT

The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs1. Retinal cell types may have evolved to accommodate these varied needs, but this has not been systematically studied. Here we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a bird, a reptile, a teleost fish and a lamprey. We found high molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells (RGCs) and Müller glia), with transcriptomic variation across species related to evolutionary distance. Major subclasses were also conserved, whereas variation among cell types within classes or subclasses was more pronounced. However, an integrative analysis revealed that numerous cell types are shared across species, based on conserved gene expression programmes that are likely to trace back to an early ancestral vertebrate. The degree of variation among cell types increased from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified rodent orthologues of midget RGCs, which comprise more than 80% of RGCs in the human retina, subserve high-acuity vision, and were previously believed to be restricted to primates2. By contrast, the mouse orthologues have large receptive fields and comprise around 2% of mouse RGCs. Projections of both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but are descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.


Subject(s)
Biological Evolution , Neurons , Retina , Vertebrates , Vision, Ocular , Animals , Humans , Neurons/classification , Neurons/cytology , Neurons/physiology , Retina/cytology , Retina/physiology , Retinal Ganglion Cells/classification , Single-Cell Gene Expression Analysis , Vertebrates/physiology , Vision, Ocular/physiology , Species Specificity , Amacrine Cells/classification , Photoreceptor Cells/classification , Ependymoglial Cells/classification , Retinal Bipolar Cells/classification , Visual Perception
2.
bioRxiv ; 2023 Apr 08.
Article in English | MEDLINE | ID: mdl-37066415

ABSTRACT

The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs (Baden et al., 2020). One might expect that retinal cell types evolved to accommodate these varied needs, but this has not been systematically studied. Here, we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a teleost fish, a bird, a reptile and a lamprey. Molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells [RGCs] and Muller glia) is striking, with transcriptomic differences across species correlated with evolutionary distance. Major subclasses are also conserved, whereas variation among types within classes or subclasses is more pronounced. However, an integrative analysis revealed that numerous types are shared across species based on conserved gene expression programs that likely trace back to the common ancestor of jawed vertebrates. The degree of variation among types increases from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified mammalian orthologs of midget RGCs, which comprise >80% of RGCs in the human retina, subserve high-acuity vision, and were believed to be primate-specific (Berson, 2008); in contrast, the mouse orthologs comprise <2% of mouse RGCs. Projections both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.

3.
J Neurosci ; 42(17): 3546-3556, 2022 04 27.
Article in English | MEDLINE | ID: mdl-35296547

ABSTRACT

The mouse primary visual cortex is a model system for understanding the relationship between cortical structure, function, and behavior (Seabrook et al., 2017; Chaplin and Margrie, 2020; Hooks and Chen, 2020; Saleem, 2020; Flossmann and Rochefort, 2021). Binocular neurons in V1 are the cellular basis of binocular vision, which is required for predation (Scholl et al., 2013; Hoy et al., 2016; La Chioma et al., 2020; Berson, 2021; Johnson et al., 2021). The normal development of binocular responses, however, has not been systematically measured. Here, we measure tuning properties of neurons to either eye in awake mice of either sex from eye opening to the closure of the critical period. At eye opening, we find an adult-like fraction of neurons responding to the contralateral-eye stimulation, which are selective for orientation and spatial frequency; few neurons respond to ipsilateral eye, and their tuning is immature. Fraction of ipsilateral-eye responses increases rapidly in the first few days after eye opening and more slowly thereafter, reaching adult levels by critical period closure. Tuning of these responses improves with a similar time course. The development and tuning of binocular responses parallel that of ipsilateral-eye responses. Four days after eye opening, monocular neurons respond to a full range of orientations but become more biased to cardinal orientations. Binocular responses, by contrast, lose their cardinal bias with age. Together, these data provide an in-depth accounting of the development of monocular and binocular responses in the binocular region of mouse V1 using a consistent set of visual stimuli and measurements.SIGNIFICANCE STATEMENT In this manuscript, we present a full accounting of the emergence and refinement of monocular and binocular receptive field tuning properties of thousands of pyramidal neurons in mouse primary visual cortex. Our data reveal new features of monocular and binocular development that revise current models on the emergence of cortical binocularity. Given the recent interest in visually guided behaviors in mice that require binocular vision (e.g., predation), our measures will provide the basis for studies on the emergence of the neural circuitry guiding these behaviors.


Subject(s)
Visual Cortex , Animals , Mice , Neurons/physiology , Photic Stimulation , Primary Visual Cortex , Vision, Binocular/physiology , Visual Cortex/physiology
4.
Cell ; 185(2): 311-327.e24, 2022 01 20.
Article in English | MEDLINE | ID: mdl-35063073

ABSTRACT

The role of postnatal experience in sculpting cortical circuitry, while long appreciated, is poorly understood at the level of cell types. We explore this in the mouse primary visual cortex (V1) using single-nucleus RNA sequencing, visual deprivation, genetics, and functional imaging. We find that vision selectively drives the specification of glutamatergic cell types in upper layers (L) (L2/3/4), while deeper-layer glutamatergic, GABAergic, and non-neuronal cell types are established prior to eye opening. L2/3 cell types form an experience-dependent spatial continuum defined by the graded expression of ∼200 genes, including regulators of cell adhesion and synapse formation. One of these genes, Igsf9b, a vision-dependent gene encoding an inhibitory synaptic cell adhesion molecule, is required for the normal development of binocular responses in L2/3. In summary, vision preferentially regulates the development of upper-layer glutamatergic cell types through the regulation of cell-type-specific gene expression programs.


Subject(s)
Vision, Ocular , Visual Cortex/cytology , Visual Cortex/embryology , Animals , Animals, Newborn , Biomarkers/metabolism , Gene Expression Profiling , Gene Expression Regulation, Developmental , Glutamic Acid/metabolism , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/cytology , RNA-Seq , Transcriptome/genetics , Vision, Binocular/genetics , gamma-Aminobutyric Acid/metabolism
5.
Curr Biol ; 31(19): 4305-4313.e5, 2021 10 11.
Article in English | MEDLINE | ID: mdl-34411526

ABSTRACT

Depth perception emerges from the development of binocular neurons in primary visual cortex. Vision is required for these neurons to acquire their mature responses to visual stimuli. The prevailing view is that vision does not influence binocular circuitry until the onset of the critical period, about a week after eye opening, and that plasticity of visual responses is triggered by increased inhibition. Here, we show that vision is required to form binocular neurons and to improve binocular tuning and matching from eye opening until critical period closure. Enhancing inhibition does not accelerate this process. Vision soon after eye opening improves the tuning properties of binocular neurons by strengthening and sharpening ipsilateral eye cortical responses. This progressively changes the population of neurons in the binocular pool, and this plasticity is sensitive to interocular differences prior to critical period onset. Thus, vision establishes binocular circuitry and guides binocular plasticity from eye opening.


Subject(s)
Visual Cortex , Neurons/physiology , Photic Stimulation , Vision, Binocular/physiology , Vision, Ocular , Visual Cortex/physiology
6.
Neuron ; 108(4): 735-747.e6, 2020 11 25.
Article in English | MEDLINE | ID: mdl-33091339

ABSTRACT

High acuity stereopsis emerges during an early postnatal critical period when binocular neurons in the primary visual cortex sharpen their receptive field tuning properties. We find that this sharpening is achieved by dismantling the binocular circuit present at critical period onset and building it anew. Longitudinal imaging of receptive field tuning (e.g., orientation selectivity) of thousands of neurons reveals that most binocular neurons present in layer 2/3 at critical period onset are poorly tuned and are rendered monocular. In parallel, new binocular neurons are established by conversion of well-tuned monocular neurons as they gain matched input from the other eye. These improvements in binocular tuning in layer 2/3 are not inherited from layer 4 but are driven by the experience-dependent sharpening of ipsilateral eye responses. Thus, vision builds a new and more sharply tuned binocular circuit in layer 2/3 by cellular exchange and not by refining the original circuit.


Subject(s)
Critical Period, Psychological , Vision, Binocular/physiology , Visual Cortex/physiology , Visual Pathways/physiology , Animals , Female , Male , Mice , Mice, Transgenic , Neurons/physiology , Orientation/physiology , Photic Stimulation , Vision, Monocular/physiology
7.
Nature ; 567(7746): 100-104, 2019 03.
Article in English | MEDLINE | ID: mdl-30787434

ABSTRACT

Sensory experience in early postnatal life, during so-called critical periods, restructures neural circuitry to enhance information processing1. Why the cortex is susceptible to sensory instruction in early life and why this susceptibility wanes with age are unclear. Here we define a developmentally restricted engagement of inhibitory circuitry that shapes localized dendritic activity and is needed for vision to drive the emergence of binocular visual responses in the mouse primary visual cortex. We find that at the peak of the critical period for binocular plasticity, acetylcholine released from the basal forebrain during periods of heightened arousal directly excites somatostatin (SST)-expressing interneurons. Their inhibition of pyramidal cell dendrites and of fast-spiking, parvalbumin-expressing interneurons enhances branch-specific dendritic responses and somatic spike rates within pyramidal cells. By adulthood, this cholinergic sensitivity is lost, and compartmentalized dendritic responses are absent but can be re-instated by optogenetic activation of SST cells. Conversely, suppressing SST cell activity during the critical period prevents the normal development of binocular receptive fields by impairing the maturation of ipsilateral eye inputs. This transient cholinergic modulation of SST cells, therefore, seems to orchestrate two features of neural plasticity-somatic disinhibition and compartmentalized dendritic spiking. Loss of this modulation may contribute to critical period closure.


Subject(s)
Action Potentials , Critical Period, Psychological , Dendrites/metabolism , Visual Cortex/cytology , Visual Cortex/physiology , Acetylcholine/metabolism , Animals , Calcium Signaling , Female , Interneurons/metabolism , Male , Mice , Neural Inhibition , Neural Pathways , Neuronal Plasticity/physiology , Ocular Physiological Phenomena , Optogenetics , Parvalbumins/metabolism , Pyramidal Cells/metabolism , Somatostatin/metabolism , Vision, Binocular/physiology
8.
Cell Rep ; 26(9): 2282-2288.e3, 2019 02 26.
Article in English | MEDLINE | ID: mdl-30811979

ABSTRACT

Brain state determines patterns of spiking output that underlie behavior. In neocortex, brain state is reflected in the spontaneous activity of the network, which is regulated in part by neuromodulatory input from the brain stem and by local inhibition. We find that fast-spiking, parvalbumin-expressing inhibitory neurons, which exert state-dependent control of network gain and spike patterns, cluster into two stable and functionally distinct subnetworks that are differentially engaged by ascending neuromodulation. One group is excited as a function of increased arousal state; this excitation is driven in part by the increase in cortical norepinephrine that occurs when the locus coeruleus is active. A second group is suppressed during movement when acetylcholine is released into the cortex via projections from the nucleus basalis. These data establish the presence of functionally independent subnetworks of Parvalbumin (PV) cells in the upper layers of the neocortex that are differentially engaged by the ascending reticular activating system.


Subject(s)
Interneurons/physiology , Neocortex/physiology , Parvalbumins/metabolism , Animals , Cholinergic Antagonists/pharmacology , Fear , Female , Interneurons/drug effects , Interneurons/metabolism , Locus Coeruleus/physiology , Male , Mice , Motor Cortex/physiology , Neocortex/metabolism , Visual Cortex/physiology
9.
J Neurophysiol ; 120(1): 274-280, 2018 07 01.
Article in English | MEDLINE | ID: mdl-29668380

ABSTRACT

Neurons in primary visual cortex are selective to the orientation and spatial frequency of sinusoidal gratings. In the classic model of cortical organization, a population of neurons responding to the same region of the visual field but tuned to all possible feature combinations provides a detailed representation of the local image. Such a functional module is assumed to be replicated across primary visual cortex to provide a uniform representation of the image across the entire visual field. In contrast, it has been hypothesized that the tiling properties of ON- and OFF-center receptive fields in the retina, largely mirrored in the geniculate, may constrain cortical tuning at each location in the visual field. This model predicts the existence of local biases in tuning that vary across the visual field and would prevent the cortex from developing a uniform, modular representation as postulated by the classic model. Here, we confirm the existence of local tuning biases in the primary visual cortex of the mouse, lending support to the notion that cortical tuning may be constrained by signals from the periphery. NEW & NOTEWORTHY Populations of cortical neurons responding to the same part of the visual field are shown to have similar tuning. Such local biases are consistent with the hypothesis that cortical tuning, in mouse primary visual cortex, is constrained by signals from the periphery.


Subject(s)
Visual Cortex , Animals , Bias , Mice , Neurons , Orientation , Visual Fields
10.
Nat Commun ; 9(1): 422, 2018 01 29.
Article in English | MEDLINE | ID: mdl-29379017

ABSTRACT

Modeling studies suggest that clustered structural plasticity of dendritic spines is an efficient mechanism of information storage in cortical circuits. However, why new clustered spines occur in specific locations and how their formation relates to learning and memory (L&M) remain unclear. Using in vivo two-photon microscopy, we track spine dynamics in retrosplenial cortex before, during, and after two forms of episodic-like learning and find that spine turnover before learning predicts future L&M performance, as well as the localization and rates of spine clustering. Consistent with the idea that these measures are causally related, a genetic manipulation that enhances spine turnover also enhances both L&M and spine clustering. Biophysically inspired modeling suggests turnover increases clustering, network sparsity, and memory capacity. These results support a hotspot model where spine turnover is the driver for localization of clustered spine formation, which serves to modulate network function, thus influencing storage capacity and L&M.


Subject(s)
Cerebral Cortex/physiology , Conditioning, Psychological , Dendritic Spines/physiology , Learning/physiology , Neuronal Plasticity/physiology , Spatial Memory/physiology , Animals , Cerebral Cortex/anatomy & histology , Dendritic Spines/pathology , Fear , Female , Intravital Microscopy , Male , Memory/physiology , Mice
11.
Nat Neurosci ; 20(3): 389-392, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28114295

ABSTRACT

Push-pull is a canonical computation of excitatory cortical circuits. By contrast, we identify a pull-push inhibitory circuit in frontal cortex that originates in vasoactive intestinal polypeptide (VIP)-expressing interneurons. During arousal, VIP cells rapidly and directly inhibit pyramidal neurons; VIP cells also indirectly excite these pyramidal neurons via parallel disinhibition. Thus, arousal exerts a feedback pull-push influence on excitatory neurons-an inversion of the canonical push-pull of feedforward input.


Subject(s)
Feedback, Physiological/physiology , Frontal Lobe/physiology , Interneurons/physiology , Neural Inhibition/physiology , Vasoactive Intestinal Peptide/physiology , Animals , Arousal/physiology , Channelrhodopsins , Female , Interneurons/metabolism , Locomotion/physiology , Male , Mice , Mice, Transgenic , Pupil/physiology , Pyramidal Cells/physiology , Vasoactive Intestinal Peptide/genetics , Vasoactive Intestinal Peptide/metabolism
12.
Nat Commun ; 7: 12829, 2016 09 09.
Article in English | MEDLINE | ID: mdl-27611660

ABSTRACT

Perisomatic inhibition of pyramidal neurons is established by fast-spiking, parvalbumin-expressing interneurons (PV cells). Failure to assemble adequate perisomatic inhibition is thought to underlie the aetiology of neurological dysfunction in seizures, autism spectrum disorders and schizophrenia. Here we show that in mouse visual cortex, strong perisomatic inhibition does not develop if PV cells lack a single copy of Pten. PTEN signalling appears to drive the assembly of perisomatic inhibition in an experience-dependent manner by suppressing the expression of EphB4; PV cells hemizygous for Pten show an ∼2-fold increase in expression of EphB4, and over-expression of EphB4 in adult PV cells causes a dismantling of perisomatic inhibition. These findings implicate a molecular disinhibitory mechanism driving the establishment of perisomatic inhibition whereby visual experience enhances Pten signalling, resulting in the suppression of EphB4 expression; this relieves a native synaptic repulsion between PV cells and pyramidal neurons, thereby promoting the assembly of perisomatic inhibition.


Subject(s)
Neurons/physiology , PTEN Phosphohydrolase/metabolism , Receptor, EphB4/metabolism , Visual Cortex/physiology , Animals , Embryo, Mammalian , Gene Deletion , Gene Expression Regulation/physiology , Light , Mice , Mutation , PTEN Phosphohydrolase/genetics , Parvalbumins/metabolism , Pyramidal Cells , Receptor, EphB4/genetics , Signal Transduction
13.
Nat Commun ; 7: 12270, 2016 08 02.
Article in English | MEDLINE | ID: mdl-27481398

ABSTRACT

The primary visual cortex of higher mammals is organized into two-dimensional maps, where the preference of cells for stimulus parameters is arranged regularly on the cortical surface. In contrast, the preference of neurons in the rodent appears to be arranged randomly, in what is termed a salt-and-pepper map. Here we revisited the spatial organization of receptive fields in mouse primary visual cortex by measuring the tuning of pyramidal neurons in the joint orientation and spatial frequency domain. We found that the similarity of tuning decreases as a function of cortical distance, revealing a weak but statistically significant spatial clustering. Clustering was also observed across different cortical depths, consistent with a columnar organization. Thus, the mouse visual cortex is not strictly a salt-and-pepper map. At least on a local scale, it resembles a degraded version of the organization seen in higher mammals, hinting at a possible common origin.


Subject(s)
Orientation/physiology , Pyramidal Cells/physiology , Visual Cortex/physiology , Visual Pathways/physiology , Visual Perception/physiology , Animals , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Animal , Models, Neurological , Photic Stimulation , Visual Cortex/cytology , Visual Fields/physiology
14.
J Neurosci ; 36(24): 6382-92, 2016 06 15.
Article in English | MEDLINE | ID: mdl-27307228

ABSTRACT

UNLABELLED: We do not fully understand how behavioral state modulates the processing and transmission of sensory signals. Here, we studied the cortical representation of the retinal image in mice that spontaneously switched between a state of rest and a constricted pupil, and one of active locomotion and a dilated pupil, indicative of heightened attention. We measured the selectivity of neurons in primary visual cortex for orientation and spatial frequency, as well as their response gain, in these two behavioral states. Consistent with prior studies, we found that preferred orientation and spatial frequency remained invariant across states, whereas response gain increased during locomotion relative to rest. Surprisingly, relative gain, defined as the ratio between the gain during locomotion and the gain during rest, was not uniform across the population. Cells tuned to high spatial frequencies showed larger relative gain compared with those tuned to lower spatial frequencies. The preferential enhancement of high-spatial-frequency information was also reflected in our ability to decode the stimulus from population activity. Finally, we show that changes in gain originate from shifts in the operating point of neurons along a spiking nonlinearity as a function of behavioral state. Differences in the relative gain experienced by neurons with high and low spatial frequencies are due to corresponding differences in how these cells shift their operating points between behavioral states. SIGNIFICANCE STATEMENT: How behavioral state modulates the processing and transmission of sensory signals remains poorly understood. Here, we show that the mean firing rate and neuronal gain increase during locomotion as a result in a shift of the operating point of neurons. We define relative gain as the ratio between the gain of neurons during locomotion and rest. Interestingly, relative gain is higher in cells with preferences for higher spatial frequencies than those with low-spatial-frequency selectivity. This means that, during a state of locomotion and heightened attention, the population activity in primary visual cortex can support better spatial acuity, a phenomenon that parallels the improved spatial resolution observed in human subjects during the allocation of spatial attention.


Subject(s)
Attention/physiology , Locomotion/physiology , Neurons/physiology , Orientation, Spatial/physiology , Visual Cortex/cytology , Visual Cortex/physiology , Action Potentials/physiology , Animals , Female , Linear Models , Male , Mice , Mice, Inbred C57BL , Photic Stimulation , Transduction, Genetic
15.
Neuron ; 87(2): 247-8, 2015 Jul 15.
Article in English | MEDLINE | ID: mdl-26182410

ABSTRACT

There has been a surge of interest in how inhibitory neurons influence the output of local circuits in the brain. In this issue of Neuron, Scholl et al. (2015) provide a compelling argument for what one class of inhibitory neurons actually does.


Subject(s)
Interneurons/physiology , Neocortex/cytology , Nerve Net/physiology , Parvalbumins/metabolism , Animals
16.
Curr Opin Neurobiol ; 35: 44-8, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26126153

ABSTRACT

Maturation of cortical inhibition just after eye opening is a necessary precedent for the emergence of competitive, experience-dependent ocular dominance plasticity in the visual cortex. What inhibition is doing in this context, though, is not clear. Here I outline new hypotheses on the roles of somatic and dendritic inhibition in the opening and closure of critical periods, and their roles in the competitive processes therein.


Subject(s)
Cerebral Cortex/physiology , Dominance, Ocular/physiology , Neural Inhibition/physiology , Neuronal Plasticity/physiology , Vision, Binocular/physiology , Vision, Monocular/physiology , Animals , Humans
17.
PLoS One ; 10(5): e0125633, 2015.
Article in English | MEDLINE | ID: mdl-25951243

ABSTRACT

The establishment and maintenance of neuronal circuits depends on tight regulation of synaptic contacts. We hypothesized that CNTNAP2, a protein associated with autism, would play a key role in this process. Indeed, we found that new dendritic spines in mice lacking CNTNAP2 were formed at normal rates, but failed to stabilize. Notably, rates of spine elimination were unaltered, suggesting a specific role for CNTNAP2 in stabilizing new synaptic circuitry.


Subject(s)
Dendritic Spines/physiology , Membrane Proteins/physiology , Nerve Tissue Proteins/physiology , Animals , Female , Male , Mice
19.
Proc Natl Acad Sci U S A ; 111(23): 8661-6, 2014 Jun 10.
Article in English | MEDLINE | ID: mdl-24912150

ABSTRACT

The retrosplenial cortex (RSC) is part of a network of interconnected cortical, hippocampal, and thalamic structures harboring spatially modulated neurons. The RSC contains head direction cells and connects to the parahippocampal region and anterior thalamus. Manipulations of the RSC can affect spatial and contextual tasks. A considerable amount of evidence implicates the role of the RSC in spatial navigation, but it is unclear whether this structure actually encodes or stores spatial information. We used a transgenic mouse in which the expression of green fluorescent protein was under the control of the immediate early gene c-fos promoter as well as time-lapse two-photon in vivo imaging to monitor neuronal activation triggered by spatial learning in the Morris water maze. We uncovered a repetitive pattern of cell activation in the RSC consistent with the hypothesis that during spatial learning an experience-dependent memory trace is formed in this structure. In support of this hypothesis, we also report three other observations. First, temporary RSC inactivation disrupts performance in a spatial learning task. Second, we show that overexpressing the transcription factor CREB in the RSC with a viral vector, a manipulation known to enhance memory consolidation in other circuits, results in spatial memory enhancements. Third, silencing the viral CREB-expressing neurons with the allatostatin system occludes the spatial memory enhancement. Taken together, these results indicate that the retrosplenial cortex engages in the formation and storage of memory traces for spatial information.


Subject(s)
Gyrus Cinguli/physiology , Hippocampus/physiology , Memory/physiology , Space Perception/physiology , Animals , Cyclic AMP Response Element-Binding Protein/metabolism , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Gyrus Cinguli/cytology , Gyrus Cinguli/metabolism , Hippocampus/cytology , Hippocampus/metabolism , Maze Learning/physiology , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Confocal/methods , Microscopy, Fluorescence, Multiphoton/methods , Neurons/cytology , Neurons/metabolism , Neurons/physiology , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins c-fos/genetics
20.
Proc Natl Acad Sci U S A ; 110(45): 18297-302, 2013 Nov 05.
Article in English | MEDLINE | ID: mdl-24145404

ABSTRACT

De novo phosphatase and tensin homolog on chromosome ten (PTEN) mutations are a cause of sporadic autism. How single-copy loss of PTEN alters neural function is not understood. Here we report that Pten haploinsufficiency increases the expression of small-conductance calcium-activated potassium channels. The resultant augmentation of this conductance increases the amplitude of the afterspike hyperpolarization, causing a decrease in intrinsic excitability. In vivo, this change in intrinsic excitability reduces evoked firing rates of cortical pyramidal neurons but does not alter receptive field tuning. The decreased in vivo firing rate is not associated with deficits in the dendritic integration of synaptic input or with changes in dendritic complexity. These findings identify calcium-activated potassium channelopathy as a cause of cortical dysfunction in the PTEN model of autism and provide potential molecular therapeutic targets.


Subject(s)
Autistic Disorder/genetics , Channelopathies/physiopathology , PTEN Phosphohydrolase/genetics , Small-Conductance Calcium-Activated Potassium Channels/metabolism , Analysis of Variance , Animals , Autistic Disorder/physiopathology , Blotting, Western , Channelopathies/genetics , Hemizygote , Humans , Mice , Mutation/genetics , Patch-Clamp Techniques , Pyramidal Tracts/cytology , Pyramidal Tracts/physiology , Small-Conductance Calcium-Activated Potassium Channels/genetics
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