Sensitive period-regulating genetic pathways and exposure to adversity shape risk for depression.

Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects on brain structure or function, behavior, and disease. Although sensitive periods for depression likely arise through a complex interplay of genes and experience, this possibility has not yet been explored in humans. We examined the effect of genetic pathways regulating sensitive periods, alone and in interaction with common childhood adversities, on depression risk. Guided by a translational approach, we: (1) performed association analyses of three gene sets (60 genes) shown in animal studies to regulate sensitive periods using summary data from a genome-wide association study of depression (n = 807,553); (2) evaluated the developmental expression patterns of these genes using data from BrainSpan (n = 31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay (dGxE) by analyzing the combined effect of common variants in sensitive period genes and time-varying exposure to two types of childhood adversity within a population-based birth cohort (n = 6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, 6 of the 15 genes in this set showed developmentally regulated gene-level expression. We also identified a statistical interaction between caregiver physical or emotional abuse during ages 1-5 years and genetic risk for depression conferred by the opening genes. Genes involved in regulating sensitive periods are differentially expressed across the life course and may be implicated in depression vulnerability. Our findings about gene-by-development interplay motivate further research in large, more diverse samples to further unravel the complexity of depression etiology through a sensitive period lens.

Regulation of auditory plasticity during critical periods and following hearing loss.

Sensory input has profound effects on neuronal organization and sensory maps in the brain. The mechanisms regulating plasticity of the auditory pathway have been revealed by examining the consequences of altered auditory input during both developmental critical periods-when plasticity facilitates the optimization of neural circuits in concert with the external environment-and in adulthood-when hearing loss is linked to the generation of tinnitus. In this review, we summarize research identifying the molecular, cellular, and circuit-level mechanisms regulating neuronal organization and tonotopic map plasticity during developmental critical periods and in adulthood. These mechanisms are shared in both the juvenile and adult brain and along the length of the auditory pathway, where they serve to regulate disinhibitory networks, synaptic structure and function, as well as structural barriers to plasticity. Regulation of plasticity also involves both neuromodulatory circuits, which link plasticity with learning and attention, as well as ascending and descending auditory circuits, which link the auditory cortex and lower structures. Further work identifying the interplay of molecular and cellular mechanisms associating hearing loss-induced plasticity with tinnitus will continue to advance our understanding of this disorder and lead to new approaches to its treatment.

All-Optical Electrophysiology Reveals the Role of Lateral Inhibition in Sensory Processing in Cortical Layer 1.

Cortical layer 1 (L1) interneurons have been proposed as a hub for attentional modulation of underlying cortex, but the transformations that this circuit implements are not known. We combined genetically targeted voltage imaging with optogenetic activation and silencing to study the mechanisms underlying sensory processing in mouse barrel cortex L1. Whisker stimuli evoked precisely timed single spikes in L1 interneurons, followed by strong lateral inhibition. A mild aversive stimulus activated cholinergic inputs and evoked a bimodal distribution of spiking responses in L1. A simple conductance-based model that only contained lateral inhibition within L1 recapitulated the sensory responses and the winner-takes-all cholinergic responses, and the model correctly predicted that the network would function as a spatial and temporal high-pass filter for excitatory inputs. Our results demonstrate that all-optical electrophysiology can reveal basic principles of neural circuit function in vivo and suggest an intuitive picture for how L1 transforms sensory and modulatory inputs. VIDEO ABSTRACT.

NMDA 2A receptors in parvalbumin cells mediate sex-specific rapid ketamine response on cortical activity.

Ketamine has emerged as a widespread treatment for a variety of psychiatric disorders when used at sub-anesthetic doses, but the neural mechanisms underlying its acute action remain unclear. Here, we identified NMDA receptors containing the 2A subunit (GluN2A) on parvalbumin (PV)-expressing inhibitory interneurons as a pivotal target of low-dose ketamine. Genetically deleting GluN2A receptors globally or selectively from PV interneurons abolished the rapid enhancement of visual cortical responses and gamma-band oscillations by ketamine. Moreover, during the follicular phase of the estrous cycle in female mice, the ketamine response was transiently attenuated along with a concomitant decrease of grin2A mRNA expression within PV interneurons. Thus, GluN2A receptors on PV interneurons mediate the immediate actions of low-dose ketamine treatment, and fluctuations in receptor expression across the estrous cycle may underlie sex-differences in drug efficacy.

Publisher Correction: Inhibitory circuit gating of auditory critical-period plasticity.

In the version of this article initially published online, the wrong version of Fig. 5 was used. There were errors in the statistical comparison brackets in Fig. 5c and the left-hand error bar in Fig. 5f. The errors have been corrected in the print, PDF and HTML versions of this article. In the version of this article initially published online and in print, the wrong version of Fig. 3h was used. There was a slight error in the alignment of the traces in the top right panel. The error has been corrected in the PDF and HTML versions of this article. The original and corrected figures are shown in the accompanying Publisher Correction.

Early Seizures Prematurely Unsilence Auditory Synapses to Disrupt Thalamocortical Critical Period Plasticity.

Heightened neural excitability in infancy and childhood results in increased susceptibility to seizures. Such early-life seizures are associated with language deficits and autism that can result from aberrant development of the auditory cortex. Here, we show that early-life seizures disrupt a critical period (CP) for tonotopic map plasticity in primary auditory cortex (A1). We show that this CP is characterized by a prevalence of "silent," NMDA-receptor (NMDAR)-only, glutamate receptor synapses in auditory cortex that become "unsilenced" due to activity-dependent AMPA receptor (AMPAR) insertion. Induction of seizures prior to this CP occludes tonotopic map plasticity by prematurely unsilencing NMDAR-only synapses. Further, brief treatment with the AMPAR antagonist NBQX following seizures, prior to the CP, prevents synapse unsilencing and permits subsequent A1 plasticity. These findings reveal that early-life seizures modify CP regulators and suggest that therapeutic targets for early post-seizure treatment can rescue CP plasticity.

Inhibitory circuit gating of auditory critical-period plasticity.

Cortical sensory maps are remodeled during early life to adapt to the surrounding environment. Both sensory and contextual signals are important for induction of this plasticity, but how these signals converge to sculpt developing thalamocortical circuits remains largely unknown. Here we show that layer 1 (L1) of primary auditory cortex (A1) is a key hub where neuromodulatory and topographically organized thalamic inputs meet to tune the cortical layers below. Inhibitory interneurons in L1 send narrowly descending projections to differentially modulate thalamic drive to pyramidal and parvalbumin-expressing (PV) cells in L4, creating brief windows of intracolumnar activation. Silencing of L1 (but not VIP-expressing) cells abolishes map plasticity during the tonotopic critical period. Developmental transitions in nicotinic acetylcholine receptor (nAChR) sensitivity in these cells caused by Lynx1 protein can be overridden to extend critical-period closure. Notably, thalamocortical maps in L1 are themselves stable, and serve as a scaffold for cortical plasticity throughout life.

Sensory integration in mouse insular cortex reflects GABA circuit maturation.

Insular cortex (IC) contributes to a variety of complex brain functions, such as communication, social behavior, and self-awareness through the integration of sensory, emotional, and cognitive content. How the IC acquires its integrative properties remains unexplored. We compared the emergence of multisensory integration (MSI) in the IC of behaviorally distinct mouse strains. While adult C57BL/6 mice exhibited robust MSI, this capacity was impaired in the inbred BTBR T+tf/J mouse model of idiopathic autism. The deficit reflected weakened γ-aminobutyric acid (GABA) circuits and compromised postnatal pruning of cross-modal input. Transient pharmacological enhancement by diazepam in BTBR mice during an early sensitive period rescued inhibition and integration in the adult IC. Moreover, impaired MSI was common across three other monogenic models (GAD65, Shank3, and Mecp2 knockout mice) displaying behavioral phenotypes and parvalbumin-circuit abnormalities. Our findings offer developmental insight into a key neural circuit relevant to neuropsychiatric conditions like schizophrenia and autism.

Balancing plasticity/stability across brain development.

The potency of the environment to shape brain function changes dramatically across the lifespan. Neural circuits exhibit profound plasticity during early life and are later stabilized. A focus on the cellular and molecular bases of these developmental trajectories has begun to unravel mechanisms, which control the onset and closure of such critical periods. Two important concepts have emerged from the study of critical periods in the visual cortex: (1) excitatory-inhibitory circuit balance is a trigger; and (2) molecular "brakes" limit adult plasticity. The onset of the critical period is determined by the maturation of specific GABA circuits. Targeting these circuits using pharmacological or genetic approaches can trigger premature onset or induce a delay. These manipulations are so powerful that animals of identical chronological age may be at the peak, before, or past their plastic window. Thus, critical period timing per se is plastic. Conversely, one of the outcomes of normal development is to stabilize the neural networks initially sculpted by experience. Rather than being passively lost, the brain's intrinsic potential for plasticity is actively dampened. This is demonstrated by the late expression of brake-like factors, which reversibly limit excessive circuit rewiring beyond a critical period. Interestingly, many of these plasticity regulators are found in the extracellular milieu. Understanding why so many regulators exist, how they interact and, ultimately, how to lift them in noninvasive ways may hold the key to novel therapies and lifelong learning.

Hearing loss differentially affects thalamic drive to two cortical interneuron subtypes.

Sensory deprivation, such as developmental hearing loss, leads to an adjustment of synaptic and membrane properties throughout the central nervous system. These changes are thought to compensate for diminished sound-evoked activity. This model predicts that compensatory changes should be synergistic with one another along each functional pathway. To test this idea, we examined the excitatory thalamic drive to two types of cortical inhibitory interneurons that display differential effects in response to developmental hearing loss. The inhibitory synapses made by fast-spiking (FS) cells are weakened by hearing loss, whereas those made by low threshold-spiking (LTS) cells remain strong but display greater short-term depression (Takesian et al. 2010). Whole-cell recordings were made from FS or LTS interneurons in a thalamocortical brain slice, and medial geniculate (MG)-evoked postsynaptic potentials were analyzed. Following hearing loss, MG-evoked net excitatory potentials were smaller than normal at FS cells but larger than normal at LTS cells. Furthermore, MG-evoked excitatory potentials displayed less short-term depression at FS cells and greater short-term depression at LTS cells. Thus deprivation-induced adjustments of excitatory synapses onto inhibitory interneurons are cell-type specific and parallel the changes made by the inhibitory afferents.

Rescue of inhibitory synapse strength following developmental hearing loss.

Inhibitory synapse dysfunction may contribute to many developmental brain disorders, including the secondary consequences of sensory deprivation. In fact, developmental hearing loss leads to a profound reduction in the strength of inhibitory postsynaptic currents (IPSCs) in the auditory cortex, and this deficit persists into adulthood. This finding is consistent with the general theory that the emergence of mature synaptic properties requires activity during development. Therefore, we tested the prediction that inhibitory strength can be restored following developmental hearing loss by boosting GABAergic transmission in vivo. Conductive or sensorineural hearing loss was induced surgically in gerbils prior to hearing onset and GABA agonists were then administered for one week. IPSCs were subsequently recorded from pyramidal neurons in a thalamocortical brain slice preparation. Administration of either a GABA(A) receptor a1 subunit specific agonist (zolpidem), or a selective GABA reuptake inhibitor (SGRI), rescued IPSC amplitude in hearing loss animals. Furthermore, this restoration persisted in adults, long after drug treatment ended. In contrast, a GABA(B) receptor agonist baclofen did not restore inhibitory strength. IPSCs could also be restored when SGRI administration began 3 weeks after sensory deprivation. Together, these results demonstrate long-lasting restoration of cortical inhibitory strength in the absence of normal experience. This suggests that in vivo GABA(A) receptor activation is sufficient to promote maturation, and this principle may extend to other developmental disorders associated with diminished inhibitory function.

Age-dependent effect of hearing loss on cortical inhibitory synapse function.

The developmental plasticity of excitatory synapses is well established, particularly as a function of age. If similar principles apply to inhibitory synapses, then we would expect manipulations during juvenile development to produce a greater effect and experience-dependent changes to persist into adulthood. In this study, we first characterized the maturation of cortical inhibitory synapse function from just before the onset of hearing through adulthood. We then examined the long-term effects of developmental conductive hearing loss (CHL). Whole cell recordings from gerbil thalamocortical brain slices revealed a significant decrease in the decay time of inhibitory currents during the first 3 mo of normal development. When assessed in adults, developmental CHL led to an enduring decrease of inhibitory synaptic strength, whereas the maturation of synaptic decay time was only delayed. Early CHL also depressed the maximum discharge rate of fast-spiking, but not low-threshold-spiking, inhibitory interneurons. We then asked whether adult onset CHL had a similar effect, but neither inhibitory current amplitude nor decay time was altered. Thus inhibitory synapse function displays a protracted development during which deficits can be induced by juvenile, but not adult, hearing loss. These long-lasting changes to inhibitory function may contribute to the auditory processing deficits associated with early hearing loss.

Presynaptic GABA(B) receptors regulate experience-dependent development of inhibitory short-term plasticity.

Short-term changes in synaptic gain support information processing throughout the CNS, yet we know little about the developmental regulation of such plasticity. Here we report that auditory experience is necessary for the normal maturation of synaptic inhibitory short-term plasticity (iSTP) in the auditory cortex, and that presynaptic GABA(B) receptors regulate this development. Moderate or severe hearing loss was induced in gerbils, and iSTP was characterized by measuring inhibitory synaptic current amplitudes in response to repetitive stimuli. We reveal a profound developmental shift of iSTP from depressing to facilitating after the onset of hearing. Even moderate hearing loss prevented this shift. This iSTP change was mediated by a specific class of inhibitory interneurons, the low-threshold spiking cells. Further, using paired recordings, we reveal that presynaptic GABA(B) receptors at interneuron-pyramidal connections regulate iSTP in an experience-dependent manner. This novel synaptic mechanism may support the emergence of mature temporal processing in the auditory cortex.

Developmental hearing loss disrupts synaptic inhibition: implications for auditory processing.

Hearing loss during development leads to central deficits that persist even after the restoration of peripheral function. One key class of deficits is due to changes in central inhibitory synapses, which play a fundamental role in all aspects of auditory processing. This review focuses on the anatomical and physiological alterations of inhibitory connections at several regions within the central auditory pathway following hearing loss. Such aberrant inhibitory synaptic function may be linked to deficits in encoding binaural and spectral cues. Understanding the cellular changes that occur at inhibitory synapses following hearing loss may provide specific loci that can be targeted to improve function.

Hearing loss prevents the maturation of GABAergic transmission in the auditory cortex.

Inhibitory neurotransmission is a critical determinant of neuronal network gain and dynamic range, suggesting that network properties are shaped by activity during development. A previous study demonstrated that sensorineural hearing loss (SNHL) in gerbils leads to smaller inhibitory potentials in L2/3 pyramidal neurons in the thalamorecipient auditory cortex, ACx. Here, we explored the mechanisms that account for proper maturation of gamma-amino butyric acid (GABA)ergic transmission. SNHL was induced at postnatal day (P) 10, and whole-cell voltage-clamp recordings were obtained from layer 2/3 pyramidal neurons in thalamocortical slices at P16-19. SNHL led to an increase in the frequency of GABAzine-sensitive (antagonist) spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs), accompanied by diminished amplitudes and longer durations. Consistent with this, the amplitudes of minimum-evoked IPSCs were also reduced while their durations were longer. The alpha1- and beta2/3 subunit-specific agonists zolpidem and loreclezole increased control but not SNHL sIPSC durations. To test whether SNHL affected the maturation of GABAergic transmission, sIPSCs were recorded at P10. These sIPSCs resembled the long SNHL sIPSCs. Furthermore, zolpidem and loreclezole were ineffective in increasing their durations. Together, these data strongly suggest that the presynaptic release properties and expression of key postsynaptic GABA(A) receptor subunits are coregulated by hearing.