Joshua T. Trachtenberg

Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex

Do new synapses form in the adult cortex to support experience-dependent plasticity? To address this question, we repeatedly imaged individual pyramidal neurons in the mouse barrel cortex over periods of weeks. We found that, although dendritic structure is stable, some spines appear and disappear. Spine lifetimes vary greatly: stable spines, about 50% of the population, persist for at least a month, whereas the remainder are present for a few days or less. Serial-section electron microscopy of imaged dendritic segments revealed retrospectively that spine sprouting and retraction are associated with synapse formation and elimination. Experience-dependent plasticity of cortical receptive fields was accompanied by increased synapse turnover. Our measurements suggest that sensory experience drives the formation and elimination of synapses and that these changes might underlie adaptive remodelling of neural circuits.

Transient and Persistent Dendritic Spines in the Neocortex In Vivo

Dendritic spines were imaged over days to months in the apical tufts of neocortical pyramidal neurons (layers 5 and 2/3) in vivo. A fraction of thin spines appeared and disappeared over a few days, while most thick spines persisted for months. In the somatosensory cortex, from postnatal day (PND) 16 to PND 25 spine retractions exceeded additions, resulting in a net loss of spines. The fraction of persistent spines (lifetime > or = 8 days) grew gradually during development and into adulthood (PND 16-25, 35%; PND 35-80, 54%; PND 80-120, 66%; PND 175-225, 73%), providing evidence that synaptic circuits continue to stabilize even in the adult brain, long after the closure of known critical periods. In 6-month-old mice, spines turn over more slowly in visual compared to somatosensory cortex, possibly reflecting differences in the capacity for experience-dependent plasticity in these brain regions.

Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits

Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2(-/-) mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.

Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice

Disrupted-in-schizophrenia 1 (DISC1) was initially discovered through a balanced translocation (1;11)(q42.1;q14.3) that results in loss of the C terminus of the DISC1 protein, a region that is thought to play an important role in brain development. Here, we use an inducible and reversible transgenic system to demonstrate that early postnatal, but not adult induction, of a C-terminal portion of DISC1 in mice results in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, depressive-like traits, abnormal spatial working memory, and reduced sociability. Accordingly, we report that individuals in a discordant twin sample with a DISC1 haplotype, associating with schizophrenia as well as working memory impairments and reduced gray matter density, were more likely to show deficits in sociability than those without the haplotype. Our findings demonstrate that alterations in DISC1 function during brain development contribute to schizophrenia pathogenesis.

A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex.

Early sensory experience instructs the maturation of neural circuitry in the cortex. This has been studied extensively in the primary visual cortex, in which loss of vision to one eye permanently degrades cortical responsiveness to that eye, a phenomenon known as ocular dominance plasticity (ODP). Cortical inhibition mediates this process, but the precise role of specific classes of inhibitory neurons in ODP is controversial. Here we report that evoked firing rates of binocular excitatory neurons in the primary visual cortex immediately drop by half when vision is restricted to one eye, but gradually return to normal over the following twenty-four hours, despite the fact that vision remains restricted to one eye. This restoration of binocular-like excitatory firing rates after monocular deprivation results from a rapid, although transient, reduction in the firing rates of fast-spiking, parvalbumin-positive (PV) interneurons, which in turn can be attributed to a decrease in local excitatory circuit input onto PV interneurons. This reduction in PV-cell-evoked responses after monocular lid suture is restricted to the critical period for ODP and appears to be necessary for subsequent shifts in excitatory ODP. Pharmacologically enhancing inhibition at the time of sight deprivation blocks ODP and, conversely, pharmacogenetic reduction of PV cell firing rates can extend the critical period for ODP. These findings define the microcircuit changes initiating competitive plasticity during critical periods of cortical development. Moreover, they show that the restoration of evoked firing rates of layer 2/3 pyramidal neurons by PV-specific disinhibition is a key step in the progression of ODP.

Experience-dependent binocular competition in the visual cortex begins at eye opening

Visual experience begins at eye opening, but current models consider cortical circuitry to be resistant to experience-dependent competitive modification until the activation of a later critical period. Here we examine this idea using optical imaging to map the time course of receptive field refinement in normal mice, mice in which the contralateral eye never opens and mice in which the contralateral eye is silenced. We found that the refinement of ipsilateral eye retinotopy is retarded by contralateral deprivation, but accelerated by silencing of the contralateral eye. Patterned visual experience through the ipsilateral eye is required for this acceleration. These differences are most obvious at postnatal day 15, long before the start of the critical period, indicating that experience-dependent binocular plasticity occurs much earlier than was previously thought. Furthermore, these results suggest that the quality of activity, in terms of signal to noise, and not the quantity, determines robust receptive field development.

Glial Growth Factor Rescues Schwann Cells of Mechanoreceptors from Denervation-Induced Apoptosis

Golgi tendon organs and Pacinian corpuscles are peripheral mechanoreceptors that disappear after denervation during a critical period in early postnatal development. Even if regeneration is allowed to occur, Golgi tendon organs do not reform, and the reformation of Pacinian corpuscles is greatly impaired. The sensory nerve terminals of both types of mechanoreceptors are closely associated with Schwann cells. Here we investigate the changes in the Schwann cells found in Golgi tendon organs and Pacinian corpuscles after nerve resection in the early neonatal period. We report that denervation induces the apoptotic death of these Schwann cells and that this apoptosis can be prevented by administration of a soluble form of neuregulin, glial growth factor 2. Schwann cells associated with these mechanoreceptors are immunoreactive for the neuregulin receptors erbB2, erbB3, and erbB4, and the sensory nerve terminals are immunoreactive for neuregulin. Our results suggest that Schwann cells in developing sensory end organs are trophically dependent on sensory axon terminals and that an axon-derived neuregulin mediates this trophic interaction. The denervation-induced death of mechanoreceptor Schwann cells is correlated with deficiencies in the re-establishment of these sensory end organs by regenerating axons.

Laminar and compartmental regulation of dendritic growth in mature cortex

Can dendrites grow in mature cortex? We used chronic in vivo imaging to follow pyramidal neurons before and after cortical deletion of the Pten tumor suppressor gene in mature mice. We found that Pten/mTOR signaling uniquely regulates the growth of layer 2/3 apical dendrites; no effects of gene deletion were observed on basal dendrites of these pyramidal neurons or along layer 5 apical dendrites.

Fast-spiking interneurons have an initial orientation bias that is lost with vision

We found that in mice, following eye opening, fast-spiking, parvalbumin-positive GABAergic interneurons had well-defined orientation tuning preferences and that subsequent visual experience broadened this tuning. Broad inhibitory tuning was not required for the developmental sharpening of excitatory tuning but did precede binocular matching of excitatory orientation tuning. We propose that experience-dependent broadening of inhibition is a candidate for initiating the critical period of excitatory binocular plasticity in developing visual cortex.

δ-Catenin Is Required for the Maintenance of Neural Structure and Function in Mature Cortex In Vivo

Delta-catenin is a brain-specific member of the adherens junction complex that localizes to the postsynaptic and dendritic compartments. This protein is likely critical for normal cognitive function; its hemizygous loss is linked to the severe mental retardation syndrome Cri-du-Chat and it directly interacts with presenilin-1 (PS1), the protein most frequently mutated in familial Alzheimers disease. Here we examine dendritic structure and cortical function in vivo in mice lacking delta-catenin. We find that in cerebral cortex of 5-week-old mice, dendritic complexity, spine density, and cortical responsiveness are similar between mutant and littermate controls; thereafter, mutant mice experience progressive dendritic retraction, a reduction in spine density and stability, and concomitant reductions in cortical responsiveness. Our results indicate that delta-catenin regulates the maintenance of dendrites and dendritic spines in mature cortex but does not appear to be necessary for the initial establishment of these structures during development.