Dark exposure reduces high-frequency hearing loss in C57BL/6J mice.

Plastic changes in the brain are primarily limited to early postnatal periods. Recovery of adult brain plasticity is critical for the effective development of therapies. A brief (1-2 week) duration of visual deprivation (dark exposure, DE) in adult mice can trigger functional plasticity of thalamocortical and intracortical circuits in the primary auditory cortex suggesting improved sound processing. We tested if DE enhances the ability of adult mice to detect sounds. We trained and continuously evaluated the behavioral performance of mice in control and DE conditions using automated home-cage training. Consistent with age-related peripheral hearing loss present in C57BL/6J mice, we observed decreased performance for high-frequency sounds with age, which was reduced by DE. In CBA mice with preserved peripheral hearing, we also found that DE enhanced auditory performance in low and mid frequencies over time compared to the control.

Transcranial Low-Intensity Focused Ultrasound Stimulation of the Visual Thalamus Produces Long-Term Depression of Thalamocortical Synapses in the Adult Visual Cortex.

Transcranial focused ultrasound stimulation (tFUS) is a noninvasive neuromodulation technique, which can penetrate deeper and modulate neural activity with a greater spatial resolution (on the order of millimeters) than currently available noninvasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). While there are several studies demonstrating the ability of tFUS to modulate neuronal activity, it is unclear whether it can be used for producing long-term plasticity as needed to modify circuit function, especially in adult brain circuits with limited plasticity such as the thalamocortical synapses. Here we demonstrate that transcranial low-intensity focused ultrasound (LIFU) stimulation of the visual thalamus (dorsal lateral geniculate nucleus, dLGN), a deep brain structure, leads to NMDA receptor (NMDAR)-dependent long-term depression of its synaptic transmission onto layer 4 neurons in the primary visual cortex (V1) of adult mice of both sexes. This change is not accompanied by large increases in neuronal activity, as visualized using the cFos Targeted Recombination in Active Populations (cFosTRAP2) mouse line, or activation of microglia, which was assessed with IBA-1 staining. Using a model (SONIC) based on the neuronal intramembrane cavitation excitation (NICE) theory of ultrasound neuromodulation, we find that the predicted activity pattern of dLGN neurons upon sonication is state-dependent with a range of activity that falls within the parameter space conducive for inducing long-term synaptic depression. Our results suggest that noninvasive transcranial LIFU stimulation has a potential for recovering long-term plasticity of thalamocortical synapses in the postcritical period adult brain.

Selective plasticity of fast and slow excitatory synapses on somatostatin interneurons in adult visual cortex.

Somatostatin-positive (SOM) interneurons are integral for shaping cortical processing and their dynamic recruitment is likely necessary for adaptation to sensory experience and contextual information. We found that excitatory synapses on SOMs in layer 2/3 (L2/3) of primary visual cortex (V1) of mice can be categorized into fast (F)- and slow (S)-Types based on the kinetics of the AMPA receptor-mediated current. Each SOM contains both types of synapses in varying proportions. The majority of local pyramidal neurons (PCs) make unitary connections with SOMs using both types, followed by those utilizing only S-Type, and a minority with only F-Type. Sensory experience differentially regulates synapses on SOMs, such that local F-Type synapses change with visual deprivation and S-Type synapses undergo plasticity with crossmodal auditory deprivation. Our results demonstrate that the two types of excitatory synapses add richness to the SOM circuit recruitment and undergo selective plasticity enabling dynamic adaptation of the adult V1.

Mouse models of SYNGAP1-related intellectual disability.

SYNGAP1 is a Ras-GTPase-activating protein highly enriched at excitatory synapses in the brain. De novo loss-of-function mutations in SYNGAP1 are a major cause of genetically defined neurodevelopmental disorders (NDDs). These mutations are highly penetrant and cause SYNGAP1-related intellectual disability (SRID), an NDD characterized by cognitive impairment, social deficits, early-onset seizures, and sleep disturbances. Studies in rodent neurons have shown that Syngap1 regulates developing excitatory synapse structure and function, and heterozygous Syngap1 knockout mice have deficits in synaptic plasticity, learning, and memory and have seizures. However, how specific SYNGAP1 mutations found in humans lead to disease has not been investigated in vivo. To explore this, we utilized the CRISPR-Cas9 system to generate knock-in mouse models with two distinct known causal variants of SRID: one with a frameshift mutation leading to a premature stop codon, SYNGAP1; L813RfsX22, and a second with a single-nucleotide mutation in an intron that creates a cryptic splice acceptor site leading to premature stop codon, SYNGAP1; c.3583-9G>A. While reduction in Syngap1 mRNA varies from 30 to 50% depending on the specific mutation, both models show ~50% reduction in Syngap1 protein, have deficits in synaptic plasticity, and recapitulate key features of SRID including hyperactivity and impaired working memory. These data suggest that half the amount of SYNGAP1 protein is key to the pathogenesis of SRID. These results provide a resource to study SRID and establish a framework for the development of therapeutic strategies for this disorder.

Exuberant de novo dendritic spine growth in mature neurons.

Dendritic spines are structural correlates of excitatory synapses maintaining stable synaptic communications. However, this strong spine-synapse relationship was mainly characterized in excitatory pyramidal neurons (PyNs), raising a possibility that inferring synaptic density from dendritic spine number may not be universally applied to all neuronal types. Here we found that the ectopic expression of H-Ras increased dendritic spine numbers regardless of cortical cell types such as layer 2/3 pyramidal neurons (PyNs), parvalbumin (PV)- and vasoactive intestinal peptide (VIP)-positive interneurons (INs) in the primary motor cortex (M1). The probability of detecting dendritic spines was positively correlated with the magnitude of H-Ras activity, suggesting elevated local H-Ras activity is involved in the process of dendritic spine formation. H-Ras overexpression caused high spine turnover rate via adding more spines rather than eliminating them. Two-photon photolysis of glutamate triggered de novo dendritic spine formation in mature neurons, suggesting H-Ras induced spine formation is not restricted to the early development. In PyNs and PV-INs, but not VIP-INs, we observed a shift in average spine neck length towards longer filopodia-like phenotypes. The portion of dendritic spines lacking key excitatory synaptic proteins were significantly increased in H-Ras transfected neurons, suggesting that these increased spines have other distinct functions. High spine density caused by H-Ras did not result in change in the frequency or the amplitude of miniature excitatory postsynaptic currents (mEPSCs). Thus, our results propose that dendritic spines possess more multifaceted functions beyond the morphological proxy of excitatory synapse.

Mouse models of SYNGAP1 -related intellectual disability.

SYNGAP1 is a Ras-GTPase activating protein highly enriched at excitatory synapses in the brain. De novo loss-of-function mutations in SYNGAP1 are a major cause of genetically defined neurodevelopmental disorders (NDD). These mutations are highly penetrant and cause SYNGAP1 -related intellectual disability (SRID), a NDD characterized by cognitive impairment, social deficits, early-onset seizures, and sleep disturbances (1-5). Studies in rodent neurons have shown that Syngap1 regulates developing excitatory synapse structure and function (6-11), and heterozygous Syngap1 knockout mice have deficits in synaptic plasticity, learning and memory, and have seizures (9, 12-14). However, how specific SYNGAP1 mutations found in humans lead to disease has not been investigated in vivo. To explore this, we utilized the CRISPR-Cas9 system to generate knock-in mouse models with two distinct known causal variants of SRID: one with a frameshift mutation leading to a premature stop codon, SYNGAP1; L813RfsX22, and a second with a single-nucleotide mutation in an intron that creates a cryptic splice acceptor site leading to premature stop codon, SYNGAP1; c.3583-9G>A . While reduction in Syngap1 mRNA varies from 30-50% depending on the specific mutation, both models show ∼50% reduction in Syngap1 protein, have deficits in synaptic plasticity, and recapitulate key features of SRID including hyperactivity and impaired working memory. These data suggest that half the amount of SYNGAP1 protein is key to the pathogenesis of SRID. These results provide a resource to study SRID and establish a framework for the development of therapeutic strategies for this disorder. Significance Statement: SYNGAP1 is a protein enriched at excitatory synapses in the brain that is an important regulator of synapse structure and function. SYNGAP1 mutations cause SYNGAP1 -related intellectual disability (SRID), a neurodevelopmental disorder with cognitive impairment, social deficits, seizures, and sleep disturbances. To explore how SYNGAP1 mutations found in humans lead to disease, we generated the first knock-in mouse models with causal SRID variants: one with a frameshift mutation and a second with an intronic mutation that creates a cryptic splice acceptor site. Both models show decreased Syngap1 mRNA and Syngap1 protein and recapitulate key features of SRID including hyperactivity and impaired working memory. These results provide a resource to study SRID and establish a framework for the development of therapeutic strategies. Highlights: Two mouse models with SYNGAP1 -related intellectual disability (SRID) mutations found in humans were generated: one with a frameshift mutation that results in a premature stop codon and the other with an intronic mutation resulting in a cryptic splice acceptor site and premature stop codon. Both SRID mouse models show 35∼50% reduction in mRNA and ∼50% reduction in Syngap1 protein.Both SRID mouse models display deficits in synaptic plasticity and behavioral phenotypes found in people. RNA-seq confirmed cryptic splice acceptor activity in one SRID mouse model and revealed broad transcriptional changes also identified in Syngap1 +/- mice. Novel SRID mouse models generated here provide a resource and establish a framework for development of future therapeutic intervention.

mGluR-dependent plasticity in rodent models of Alzheimer's disease.

Long-term potentiation (LTP) and depression (LTD) are currently the most comprehensive models of synaptic plasticity models to subserve learning and memory. In the CA1 region of the hippocampus LTP and LTD can be induced by the activation of either NMDA receptors or mGluR5 metabotropic glutamate receptors. Alterations in either form of synaptic plasticity, NMDAR-dependent or mGluR-dependent, are attractive candidates to contribute to learning deficits in conditions like Alzheimer's disease (AD) and aging. Research, however, has focused predominantly on NMDAR-dependent forms of LTP and LTD. Here we studied age-associated changes in mGluR-dependent LTP and LTD in the APP/PS1 mouse model of AD and in Octodon degu, a rodent model of aging that exhibits features of AD. At 2 months of age, APP/PS1 mouse exhibited robust mGluR-dependent LTP and LTD that was completely lost by the 8th month of age. The expression of mGluR protein in the hippocampus of APP/PS1 mice was not affected, consistent with previous findings indicating the uncoupling of the plasticity cascade from mGluR5 activation. In O. degu, the average mGluR-LTD magnitude is reduced by half by the 3 rd year of age. In aged O. degu individuals, the reduced mGluR-LTD correlated with reduced performance in a radial arm maze task. Altogether these findings support the idea that the preservation of mGluR-dependent synaptic plasticity is essential for the preservation of learning capacity during aging.

Visual Deprivation Selectively Reduces Thalamic Reticular Nucleus-Mediated Inhibition of the Auditory Thalamus in Adults.

Sensory loss leads to widespread cross-modal plasticity across brain areas to allow the remaining senses to guide behavior. While multimodal sensory interactions are often attributed to higher-order sensory areas, cross-modal plasticity has been observed at the level of synaptic changes even across primary sensory cortices. In particular, vision loss leads to widespread circuit adaptation in the primary auditory cortex (A1) even in adults. Here we report using mice of both sexes in which cross-modal plasticity occurs even earlier in the sensory-processing pathway at the level of the thalamus in a modality-selective manner. A week of visual deprivation reduced inhibitory synaptic transmission from the thalamic reticular nucleus (TRN) to the primary auditory thalamus (MGBv) without changes to the primary visual thalamus (dLGN). The plasticity of TRN inhibition to MGBv was observed as a reduction in postsynaptic gain and short-term depression. There was no observable plasticity of the cortical feedback excitatory synaptic transmission from the primary visual cortex to dLGN or TRN and A1 to MGBv, which suggests that the visual deprivation-induced plasticity occurs predominantly at the level of thalamic inhibition. We provide evidence that visual deprivation-induced change in the short-term depression of TRN inhibition to MGBv involves endocannabinoid CB1 receptors. TRN inhibition is considered critical for sensory gating, selective attention, and multimodal performances; hence, its plasticity has implications for sensory processing. Our results suggest that selective disinhibition and altered short-term dynamics of TRN inhibition in the spared thalamic nucleus support cross-modal plasticity in the adult brain.SIGNIFICANCE STATEMENT Losing vision triggers adaptation of the brain to enhance the processing of the remaining senses, which can be observed as better auditory performance in blind subjects. We previously found that depriving vision of adult rodents produces widespread circuit reorganization in the primary auditory cortex and enhances auditory processing at a neural level. Here we report that visual deprivation-induced plasticity in adults occurs much earlier in the auditory pathway, at the level of thalamic inhibition. Sensory processing is largely gated at the level of the thalamus via strong cortical feedback inhibition mediated through the thalamic reticular nucleus (TRN). We found that TRN inhibition of the auditory thalamus is selectively reduced by visual deprivation, thus playing a role in adult cross-modal plasticity.

Norepinephrine potentiates and serotonin depresses visual cortical responses by transforming eligibility traces.

Reinforcement allows organisms to learn which stimuli predict subsequent biological relevance. Hebbian mechanisms of synaptic plasticity are insufficient to account for reinforced learning because neuromodulators signaling biological relevance are delayed with respect to the neural activity associated with the stimulus. A theoretical solution is the concept of eligibility traces (eTraces), silent synaptic processes elicited by activity which upon arrival of a neuromodulator are converted into a lasting change in synaptic strength. Previously we demonstrated in visual cortical slices the Hebbian induction of eTraces and their conversion into LTP and LTD by the retroactive action of norepinephrine and serotonin Here we show in vivo in mouse V1 that the induction of eTraces and their conversion to LTP/D by norepinephrine and serotonin respectively potentiates and depresses visual responses. We also show that the integrity of this process is crucial for ocular dominance plasticity, a canonical model of experience-dependent plasticity.

Auditory Behavior in Adult-Blinded Mice.

Cross-modal plasticity occurs when the function of remaining senses is enhanced following deprivation or loss of a sensory modality. Auditory neural responses are enhanced in the auditory cortex, including increased sensitivity and frequency selectivity, following short-term visual deprivation in adult mice (Petrus et al. Neuron 81:664-673, 2014). Whether or not these visual deprivation-induced neural changes translate into improved auditory perception and performance remains unclear. As an initial investigation of the effects of adult visual deprivation on auditory behaviors, CBA/CaJ mice underwent binocular enucleation at 3-4 weeks old and were tested on a battery of learned behavioral tasks, acoustic startle response (ASR), and prepulse inhibition (PPI) tests beginning at least 2 weeks after the enucleation procedure. Auditory brain stem responses (ABRs) were also measured to screen for potential effects of visual deprivation on non-behavioral hearing function. Control and enucleated mice showed similar tone detection sensitivity and frequency discrimination in a conditioned lick suppression test. Both groups showed normal reactivity to sound as measured by ASR in a quiet background. However, when startle-eliciting stimuli were presented in noise, enucleated mice showed decreased ASR amplitude relative to controls. Control and enucleated mice displayed no significant differences in ASR habituation, PPI tests, or ABR thresholds, or wave morphology. Our findings suggest that while adult-onset visual deprivation induces cross-modal plasticity at the synaptic and circuit levels, it does not substantially influence simple auditory behavioral performance.

Metaplasticity framework for cross-modal synaptic plasticity in adults.

Sensory loss leads to widespread adaptation of neural circuits to mediate cross-modal plasticity, which allows the organism to better utilize the remaining senses to guide behavior. While cross-modal interactions are often thought to engage multisensory areas, cross-modal plasticity is often prominently observed at the level of the primary sensory cortices. One dramatic example is from functional imaging studies in humans where cross-modal recruitment of the deprived primary sensory cortex has been observed during the processing of the spared senses. In addition, loss of a sensory modality can lead to enhancement and refinement of the spared senses, some of which have been attributed to compensatory plasticity of the spared sensory cortices. Cross-modal plasticity is not restricted to early sensory loss but is also observed in adults, which suggests that it engages or enables plasticity mechanisms available in the adult cortical circuit. Because adult cross-modal plasticity is observed without gross anatomical connectivity changes, it is thought to occur mainly through functional plasticity of pre-existing circuits. The underlying cellular and molecular mechanisms involve activity-dependent homeostatic and Hebbian mechanisms. A particularly attractive mechanism is the sliding threshold metaplasticity model because it innately allows neurons to dynamically optimize their feature selectivity. In this mini review, I will summarize the cellular and molecular mechanisms that mediate cross-modal plasticity in the adult primary sensory cortices and evaluate the metaplasticity model as an effective framework to understand the underlying mechanisms.

Cortical and Subcortical Circuits for Cross-Modal Plasticity Induced by Loss of Vision.

Cortical areas are highly interconnected both via cortical and subcortical pathways, and primary sensory cortices are not isolated from this general structure. In primary sensory cortical areas, these pre-existing functional connections serve to provide contextual information for sensory processing and can mediate adaptation when a sensory modality is lost. Cross-modal plasticity in broad terms refers to widespread plasticity across the brain in response to losing a sensory modality, and largely involves two distinct changes: cross-modal recruitment and compensatory plasticity. The former involves recruitment of the deprived sensory area, which includes the deprived primary sensory cortex, for processing the remaining senses. Compensatory plasticity refers to plasticity in the remaining sensory areas, including the spared primary sensory cortices, to enhance the processing of its own sensory inputs. Here, we will summarize potential cellular plasticity mechanisms involved in cross-modal recruitment and compensatory plasticity, and review cortical and subcortical circuits to the primary sensory cortices which can mediate cross-modal plasticity upon loss of vision.

Naturalistic Spike Trains Drive State-Dependent Homeostatic Plasticity in Superficial Layers of Visual Cortex.

The history of neural activity determines the synaptic plasticity mechanisms employed in the brain. Previous studies report a rapid reduction in the strength of excitatory synapses onto layer 2/3 (L2/3) pyramidal neurons of the primary visual cortex (V1) following two days of dark exposure and subsequent re-exposure to light. The abrupt increase in visually driven activity is predicted to drive homeostatic plasticity, however, the parameters of neural activity that trigger these changes are unknown. To determine this, we first recorded spike trains in vivo from V1 layer 4 (L4) of dark exposed (DE) mice of both sexes that were re-exposed to light through homogeneous or patterned visual stimulation. We found that delivering the spike patterns recorded in vivo to L4 of V1 slices was sufficient to reduce the amplitude of miniature excitatory postsynaptic currents (mEPSCs) of V1 L2/3 neurons in DE mice, but not in slices obtained from normal reared (NR) controls. Unexpectedly, the same stimulation pattern produced an up-regulation of mEPSC amplitudes in V1 L2/3 neurons from mice that received 2 h of light re-exposure (LE). A Poisson spike train exhibiting the same average frequency as the patterns recorded in vivo was equally effective at depressing mEPSC amplitudes in L2/3 neurons in V1 slices prepared from DE mice. Collectively, our results suggest that the history of visual experience modifies the responses of V1 neurons to stimulation and that rapid homeostatic depression of excitatory synapses can be driven by non-patterned input activity.

Mechanisms of Homeostatic Synaptic Plasticity in vivo.

Synapses undergo rapid activity-dependent plasticity to store information, which when left uncompensated can lead to destabilization of neural function. It has been well documented that homeostatic changes, which operate at a slower time scale, are required to maintain stability of neural networks. While there are many mechanisms that can endow homeostatic control, sliding threshold and synaptic scaling are unique in that they operate by providing homeostatic control of synaptic strength. The former mechanism operates by adjusting the threshold for synaptic plasticity, while the latter mechanism directly alters the gain of synapses. Both modes of homeostatic synaptic plasticity have been studied across various preparations from reduced in vitro systems, such as neuronal cultures, to in vivo intact circuitry. While most of the cellular and molecular mechanisms of homeostatic synaptic plasticity have been worked out using reduced preparations, there are unique challenges present in intact circuitry in vivo, which deserve further consideration. For example, in an intact circuit, neurons receive distinct set of inputs across their dendritic tree which carry unique information. Homeostatic synaptic plasticity in vivo needs to operate without compromising processing of these distinct set of inputs to preserve information processing while maintaining network stability. In this mini review, we will summarize unique features of in vivo homeostatic synaptic plasticity, and discuss how sliding threshold and synaptic scaling may act across different activity regimes to provide homeostasis.

Temporary Visual Deprivation Causes Decorrelation of Spatiotemporal Population Responses in Adult Mouse Auditory Cortex.

Although within-modality sensory plasticity is limited to early developmental periods, cross-modal plasticity can occur even in adults. In vivo electrophysiological studies have shown that transient visual deprivation (dark exposure, DE) in adult mice improves the frequency selectivity and discrimination of neurons in thalamorecipient layer 4 (L4) of primary auditory cortex (A1). Since sound information is processed hierarchically in A1 by populations of neurons, we investigated whether DE alters network activity in A1 L4 and layer 2/3 (L2/3). We examined neuronal populations in both L4 and L2/3 using in vivo two-photon calcium (Ca2+) imaging of transgenic mice expressing GCaMP6s. We find that one week of DE in adult mice increased the sound evoked responses and frequency selectivity of both L4 and L2/3 neurons. Moreover, after DE the frequency representation changed with L4 and L2/3 showing a reduced representation of cells with best frequencies (BFs) between 8 and 16 kHz and an increased representation of cells with BFs above 32 kHz. Cells in L4 and L2/3 showed decreased pairwise signal correlations (SCs) consistent with sharper tuning curves. The decreases in SCs were larger in L4 than in L2/3. The decreased pairwise correlations indicate a sparsification of A1 responses to tonal stimuli. Thus, cross-modal experience in adults can both alter the sound-evoked responses of A1 neurons and change activity correlations within A1 potentially enhancing the encoding of auditory stimuli.

Input-Specific Metaplasticity in the Visual Cortex Requires Homer1a-Mediated mGluR5 Signaling.

Effective sensory processing depends on sensory experience-dependent metaplasticity, which allows homeostatic maintenance of neural network activity and preserves feature selectivity. Following a strong increase in sensory drive, plasticity mechanisms that decrease the strength of excitatory synapses are preferentially engaged to maintain stability in neural networks. Such adaptation has been demonstrated in various model systems, including mouse primary visual cortex (V1), where excitatory synapses on layer 2/3 (L2/3) neurons undergo rapid reduction in strength when visually deprived mice are reexposed to light. Here, we report that this form of plasticity is specific to intracortical inputs to V1 L2/3 neurons and depends on the activity of NMDA receptors (NMDARs) and group I metabotropic glutamate receptor 5 (mGluR5). Furthermore, we found that expression of the immediate early gene (IEG) Homer1a (H1a) and its subsequent interaction with mGluR5s are necessary for this input-specific metaplasticity.

Disruption of NMDAR Function Prevents Normal Experience-Dependent Homeostatic Synaptic Plasticity in Mouse Primary Visual Cortex.

Homeostatic regulation of synaptic strength allows for maintenance of neural activity within a dynamic range for proper circuit function. There are largely two distinct modes of synaptic plasticity that allow for homeostatic adaptation of cortical circuits: synaptic scaling and sliding threshold (BCM theory). Previous findings suggest that the induction of synaptic scaling is not prevented by blocking NMDARs, whereas the sliding threshold model posits that the synaptic modification threshold of LTP and LTD readjusts with activity and thus the outcome of synaptic plasticity is NMDAR dependent. Although synaptic scaling and sliding threshold have been considered two distinct mechanisms, there are indications from recent studies that these two modes of homeostatic plasticity may interact or that they may operate under two distinct activity regimes. Here, we report using both sexes of mouse that acute genetic knock-out of the obligatory subunit of NMDAR or acute pharmacological block of NMDAR prevents experience-dependent homeostatic regulation of AMPAR-mediated miniature EPSCs in layer 2/3 of visual cortex. This was not due to gross changes in postsynaptic neuronal activity with inhibiting NMDAR function as determine by c-Fos expression and two-photon Ca2+ imaging in awake mice. Our results suggest that experience-dependent homeostatic regulation of intact cortical circuits is mediated by NMDAR-dependent plasticity mechanisms, which supports a sliding threshold model of homeostatic adaptation.SIGNIFICANCE STATEMENT Prolonged changes in sensory experience lead to homeostatic adaptation of excitatory synaptic strength in sensory cortices. Both sliding threshold and synaptic scaling models can account for the observed homeostatic synaptic plasticity. Here we report that visual experience-dependent homeostatic plasticity of excitatory synapses observed in superficial layers of visual cortex is dependent on NMDAR function. In particular, both strengthening of synapses induced by visual deprivation and the subsequent weakening by reinstatement of visual experience were prevented in the absence of functional NMDARs. Our results suggest that sensory experience-dependent homeostatic adaptation depends on NMDARs, which supports the sliding threshold model of plasticity and input-specific homeostatic control observed in vivo.

Homer1a Is Required for Establishment of Contralateral Bias and Maintenance of Ocular Dominance in Mouse Visual Cortex.

It is well established across many species that neurons in the primary visual cortex (V1) display preference for visual input from one eye or the other, which is termed ocular dominance (OD). In rodents, V1 neurons exhibit a strong bias toward the contralateral eye. Molecular mechanisms of how OD is established and later maintained by plastic changes are largely unknown. Here we report a novel role of an activity-dependent immediate early gene Homer1a (H1a) in these processes. Using both sexes of H1a knock-out (KO) mice, we found that there is basal reduction in the OD index of V1 neurons measured using intrinsic signal imaging. This was because of a reduction in the strength of inputs from the contralateral eye, which is normally dominant in mice. The abnormal basal OD index was not dependent on visual experience and is driven by postnatal expression of H1a. Despite this, H1a KOs still exhibited normal shifts in OD index following a short-term (2-3 d) monocular deprivation (MD) of the contralateral eye with lid suture. However, unlike wild-type counterparts, H1a KOs continued to shift OD index with a longer duration (5-6 d) of MD. The same phenotype was recapitulated in a mouse model that has reduced Homer1 binding to metabotropic glutamate receptor 5 (mGluR5). Our results suggest a novel role of H1a and its interaction with mGluR5 in strengthening contralateral eye inputs during postnatal development to establish normal contralateral bias in mouse V1 without much impact on OD shift with brief MD.SIGNIFICANCE STATEMENT Visual cortical neurons display varying degree of responsiveness to visual stimuli through each eye, which determines their ocular dominance (OD). Molecular mechanisms responsible for establishing normal OD are largely unknown. Development of OD has been shown to be largely independent of visual experience, but guided by molecular cues and spontaneous activity. We found that activity-dependent immediate early gene H1a is critical for establishing normal OD in V1 of mice, which show contralateral eye dominance. Despite the weaker contralateral bias, H1aKOs undergo largely normal OD plasticity. The basic phenotype of H1aKO was recapitulated by mGluR5 mutation that severely reduces H1a interaction. Our results suggest a novel role of mGluR5-H1a interaction in strengthening contralateral eye inputs to V1 during postnatal development.

Disrupted AMPA Receptor Function upon Genetic- or Antibody-Mediated Loss of Autism-Associated CASPR2.

Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is CNTNAP2 encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan's syndrome, and limbic encephalitis. Despite the clear implication of CNTNAP2 and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression in vitro or in vivo decreases the synaptic expression of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling in vitro and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in CNTNAP2 may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.