Light Affects Mood and Learning through Distinct Retina-Brain Pathways.

Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN's pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning.

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.

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.

All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity.

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected form of experience-dependent circuit plasticity. In the layer 2/3 of mouse visual cortex, monocular deprivation triggers a complete, "all-or-none," elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (Pyr→PV). This binary form of circuit plasticity is unique, as it is transient, local, and discrete. It lasts only 1 d, and it does not manifest as widespread changes in synaptic strength; rather, only about half of local connections are lost, and the remaining ones are not affected in strength. Mechanistically, the deprivation-induced loss of Pyr→PV is contingent on a reduction of the protein neuropentraxin2. Functionally, the loss of Pyr→PV is absolutely necessary for ocular dominance plasticity, a canonical model of deprivation-induced model of cortical remodeling. We surmise, therefore, that this all-or-none loss of local Pyr→PV circuitry gates experience-dependent cortical plasticity.

Dysregulation of ErbB4 Signaling Pathway in the Dorsal Hippocampus after Neonatal Hypoxia-Ischemia and Late Deficits in PV+ Interneurons, Synaptic Plasticity and Working Memory.

Neonatal hypoxic-ischemic (HI) injury leads to deficits in hippocampal parvalbumin (PV)+ interneurons (INs) and working memory. Therapeutic hypothermia (TH) does not prevent these deficits. ErbB4 supports maturation and maintenance of PV+ IN. Thus, we hypothesized that neonatal HI leads to persistent deficits in PV+ INs, working memory and synaptic plasticity associated with ErbB4 dysregulation despite TH. P10 HI-injured mice were randomized to normothermia (NT, 36 °C) or TH (31 °C) for 4 h and compared to sham. Hippocampi were studied for α-fodrin, glial fibrillary acidic protein (GFAP), and neuroregulin (Nrg) 1 levels; erb-b2 receptor tyrosine kinase 4 (ErbB4)/ Ak strain transforming (Akt) activation; and PV, synaptotagmin (Syt) 2, vesicular-glutamate transporter (VGlut) 2, Nrg1, and ErbB4 expression in coronal sections. Extracellular field potentials and behavioral testing were performed. At P40, deficits in PV+ INs correlated with impaired memory and coincided with blunted long-term depression (LTD), heightened long-term potentiation (LTP) and increased Vglut2/Syt2 ratio, supporting excitatory-inhibitory (E/I) imbalance. Hippocampal Nrg1 levels were increased in the hippocampus 24 h after neonatal HI, delaying the decline documented in shams. Paradoxically ErbB4 activation decreased 24 h and again 30 days after HI. Neonatal HI leads to persistent deficits in hippocampal PV+ INs, memory, and synaptic plasticity. While acute decreased ErbB4 activation supports impaired maturation and survival after HI, late deficit reemergence may impair PV+ INs maintenance after HI.

Brief Novel Visual Experience Fundamentally Changes Synaptic Plasticity in the Mouse Visual Cortex.

LTP has been known to be a mechanism by which experience modifies synaptic responses in the neocortex. Visual deprivation in the form of dark exposure or dark rearing from birth enhances NMDAR-dependent LTP in layer 2/3 of visual cortex, a process often termed metaplasticity, which may involve changes in NMDAR subunit composition and function. However, the effects of reexposure to light after dark rearing from birth on LTP induction have not been explored. Here, we showed that the light exposure after dark rearing revealed a novel NMDAR independent form of LTP in the layer 2/3 pyramidal cells in visual cortex of mice of both sexes, which is dependent on mGluR5 activation and is associated with intracellular Ca2+ rise, CaMKII activity, PKC activity, and intact protein synthesis. Moreover, the capacity to induce mGluR-dependent LTP is transient: it only occurs when mice of both sexes reared in the dark from birth are exposed to light for 10-12 h, and it does not occur in vision-experienced, male mice, even after prolonged exposure to dark. Thus, the mGluR5-LTP unmasked by short visual experience can only be observed after dark rearing but not after dark exposure. These results suggested that, as in hippocampus, in layer 2/3 of visual cortex, there is coexistence of two distinct activity-dependent systems of synaptic plasticity, NMDAR-LTP, and mGluR5-LTP. The mGluR5-LTP unmasked by short visual experience may play a critical role in the faster establishment of normal receptive field properties.SIGNIFICANCE STATEMENT LTP has been known to be a mechanism by which experience modifies synaptic responses in the neocortex. Visual deprivation in the form of dark exposure or dark rearing from birth enhances NMDAR-dependent LTP in layer 2/3 of visual cortex, a process often termed metaplasticity. NMDAR-dependent form of LTP in visual cortex has been well characterized. Here, we report that an NMDAR-independent form of LTP can be promoted by novel visual experience on dark-reared mice, characterized as dependent on intracellular Ca2+ rise, PKC activity, and intact protein synthesis and also requires the activation of mGluR5. These findings suggest that, in layer 2/3 of visual cortex, as in hippocampus, there is coexistence of two distinct activity-dependent systems of synaptic plasticity.

Delayed injury of hippocampal interneurons after neonatal hypoxia-ischemia and therapeutic hypothermia in a murine model.

Delayed hippocampal injury and memory impairments follow neonatal hypoxia-ischemia (HI) despite the use of therapeutic hypothermia (TH). Death of hippocampal pyramidal cells occurs acutely after HI, but characterization of delayed cell death and injury of interneurons (INs) is unknown. We hypothesize that injury of INs after HI is: (i) asynchronous to that of pyramidal cells, (ii) independent of injury severity, and (iii) unresponsive to TH. HI was induced in C57BL6 mice at p10 with unilateral right carotid ligation and 45 min of hypoxia (FiO2 = 0.08). Mice were randomized to normothermia (36 °C, NT) or TH (31 °C) for 4 hr after HI and anesthesia-exposed shams were use as controls. Brains were studied at 24 hr (p11) or 8 days (p18) after HI. Vglut1, GAD65/67, PSD95, parvalbumin (PV) and calbindin-1 (Calb1) were measured. Cell death was assessed using cresyl violet staining and TUNEL assay. Hippocampal atrophy and astroglyosis at p18 were used to assess injury severity and to correlate with number of PV + INs. VGlut1 level decreased by 30% at 24 hr after HI, while GAD65/67 level decreased by ∼50% in forebrain 8 days after HI, a decrease localized in CA1 and CA3. PSD95 levels decreased in forebrain by 65% at 24 hr after HI and remained low 8 days after HI. PV + INs increased in numbers (per mm2 ) and branching between p11 and p18 in sham mice but not in NT and TH mice, resulting in 21-52% fewer PV + INs in injured mice at p18. Calb1 protein and mRNA were also reduced in HI injured mice at p18. At p18, somatodendritic attrition of INs was evident in all injured mice without evidence of cell death. Neither hippocampal atrophy nor astroglyosis correlated with the number of PV + INs at p18. Thus, HI exposure has long lasting effects in the hippocampus impairing the development of the GABAergic system with only partial protection by TH independent of the degree of hippocampal injury. © 2018 Wiley Periodicals, Inc.

Aberrant light directly impairs mood and learning through melanopsin-expressing neurons.

The daily solar cycle allows organisms to synchronize their circadian rhythms and sleep-wake cycles to the correct temporal niche. Changes in day-length, shift-work, and transmeridian travel lead to mood alterations and cognitive function deficits. Sleep deprivation and circadian disruption underlie mood and cognitive disorders associated with irregular light schedules. Whether irregular light schedules directly affect mood and cognitive functions in the context of normal sleep and circadian rhythms remains unclear. Here we show, using an aberrant light cycle that neither changes the amount and architecture of sleep nor causes changes in the circadian timing system, that light directly regulates mood-related behaviours and cognitive functions in mice. Animals exposed to the aberrant light cycle maintain daily corticosterone rhythms, but the overall levels of corticosterone are increased. Despite normal circadian and sleep structures, these animals show increased depression-like behaviours and impaired hippocampal long-term potentiation and learning. Administration of the antidepressant drugs fluoxetine or desipramine restores learning in mice exposed to the aberrant light cycle, suggesting that the mood deficit precedes the learning impairments. To determine the retinal circuits underlying this impairment of mood and learning, we examined the behavioural consequences of this light cycle in animals that lack intrinsically photosensitive retinal ganglion cells. In these animals, the aberrant light cycle does not impair mood and learning, despite the presence of the conventional retinal ganglion cells and the ability of these animals to detect light for image formation. These findings demonstrate the ability of light to influence cognitive and mood functions directly through intrinsically photosensitive retinal ganglion cells.

CDK5 downregulation enhances synaptic plasticity.

CDK5 is a serine/threonine kinase that is involved in the normal function of the adult brain and plays a role in neurotransmission and synaptic plasticity. However, its over-regulation has been associated with Tau hyperphosphorylation and cognitive deficits. Our previous studies have demonstrated that CDK5 targeting using shRNA-miR provides neuroprotection and prevents cognitive deficits. Dendritic spine morphogenesis and forms of long-term synaptic plasticity-such as long-term potentiation (LTP)-have been proposed as essential processes of neuroplasticity. However, whether CDK5 participates in these processes remains controversial and depends on the experimental model. Using wild-type mice that received injections of CDK5 shRNA-miR in CA1 showed an increased LTP and recovered the PPF in deficient LTP of APPswe/PS1Δ9 transgenic mice. On mature hippocampal neurons CDK5, shRNA-miR for 12 days induced increased dendritic protrusion morphogenesis, which was dependent on Rac activity. In addition, silencing of CDK5 increased BDNF expression, temporarily increased phosphorylation of CaMKII, ERK, and CREB; and facilitated calcium signaling in neurites. Together, our data suggest that CDK5 downregulation induces synaptic plasticity in mature neurons involving Ca2+ signaling and BDNF/CREB activation.

Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone.

To date, most in vitro toxicity testing has focused on acute effects of compounds at high concentrations. This testing strategy does not reflect real-life exposures, which might contribute to long-term disease outcome. We used a 3D-human dopaminergic in vitro LUHMES cell line model to determine whether effects of short-term rotenone exposure (100 nM, 24 h) are permanent or reversible. A decrease in complex I activity, ATP, mitochondrial diameter, and neurite outgrowth were observed acutely. After compound removal, complex I activity was still inhibited; however, ATP levels were increased, cells were electrically active and aggregates restored neurite outgrowth integrity and mitochondrial morphology. We identified significant transcriptomic changes after 24 h which were not present 7 days after wash-out. Our results suggest that testing short-term exposures in vitro may capture many acute effects which cells can overcome, missing adaptive processes, and long-term mechanisms. In addition, to study cellular resilience, cells were re-exposed to rotenone after wash-out and recovery period. Pre-exposed cells maintained higher metabolic activity than controls and presented a different expression pattern in genes previously shown to be altered by rotenone. NEF2L2, ATF4, and EAAC1 were downregulated upon single hit on day 14, but unchanged in pre-exposed aggregates. DAT and CASP3 were only altered after re-exposure to rotenone, while TYMS and MLF1IP were downregulated in both single-exposed and pre-exposed aggregates. In summary, our study shows that a human cell-based 3D model can be used to assess cellular adaptation, resilience, and long-term mechanisms relevant to neurodegenerative research.

Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period.

Maturation of excitatory drive onto fast-spiking interneurons (FS INs) in the visual cortex has been implicated in the control of the timing of the critical period for ocular dominance plasticity. However, the mechanisms that regulate the strength of these synapses over cortical development are not understood. Here we use a mouse model to show that neuregulin (NRG) and the receptor tyrosine kinase erbB4 regulate the timing of the critical period. NRG1 enhanced the strength of excitatory synapses onto FS INs, which inhibited ocular dominance plasticity during the critical period but rescued plasticity in transgenics with hypoexcitable FS INs. Blocking the effects of endogenous neuregulin via inhibition of erbBs rescued ocular dominance plasticity in postcritical period adults, allowing recovery from amblyopia induced by chronic monocular deprivation. Thus, the strength of excitation onto FS INs is a key determinant of critical period plasticity and is maintained at high levels by NRG-erbB4 signaling to constrain plasticity in adulthood. SIGNIFICANCE STATEMENT: Despite decades of experimentation, the mechanisms by which critical periods of enhanced synaptic plasticity are initiated and terminated are not completely understood. Here we show that neuregulin (NRG) and the receptor tyrosine kinase erbB4 determine critical period timing by controlling the strength of excitatory synapses onto FS INs. NRG1 enhanced excitatory drive onto fast spiking interneurons, which inhibited ocular dominance plasticity in juveniles but rescued plasticity in transgenics with hypoexcitable FS INs. Blocking the effects of endogenous neuregulin via inhibition of erbBs rescued ocular dominance plasticity in adults, allowing recovery from amblyopia induced by chronic monocular deprivation. Thus, in contrast to prevailing views of the termination of the critical period, active maintenance of strong excitation onto FS INs constrains plasticity in adults.

Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus.

Activity-dependent bidirectional modifications of excitatory synaptic strength are essential for learning and storage on new memories. Research on bidirectional synaptic plasticity has largely focused on long-term potentiation (LTP) and long-term depression (LTD) mechanisms that rely on the activation of NMDA receptors. In principle, metabotropic glutamate receptors (mGluRs) are also suitable to convert synaptic activity into intracellular signals for synaptic modification. Indeed, dysfunction of a form of LTD that depends on Type I mGluRs (mGluR-LTD), but not NMDARs, has been implicated in learning deficits in aging and mouse models of several neurological conditions, including Fragile X syndrome and Alzheimer's disease. To determine whether mGluR activation can also induce LTP in the absence of NMDAR activation, we examined in hippocampal slices from rats and mice, an NMDAR-independent form of LTP previously characterized as dependent on voltage-gated Ca(2+) channels. We found that this form of LTP requires activation of Type I mGluRs and, like mGluR-LTD but unlike NMDAR-dependent plasticity, depends crucially on protein synthesis controlled by fragile X mental retardation protein and on Arc signaling. Based on these observations, we propose the coexistence of two distinct activity-dependent systems of bidirectional synaptic plasticity: one that is based on the activity of NMDARs and the other one based on the activation of mGluRs. SIGNIFICANCE STATEMENT: Bidirectional changes of synaptic strength are crucial for the encoding of new memories. Currently, the only activity-dependent mechanism known to support such bidirectional changes are long-term potentiation (LTP) and long-term depression (LTD) forms that relay on the activation of NMDA receptors. Metabotropic glutamate receptors (mGluRs) are, in principle, also suitable to trigger bidirectional synaptic modifications. However, only the mGluR-dependent form of LTD has been characterized. Here we report that an NMDAR-independent form of LTP, initially characterized as dependent on voltage-gated Ca(2+) channels, also requires the activation of mGluRs. These finding suggest the coexistence of two distinct activity-dependent systems of bidirectional synaptic plasticity: one that is based on the activity of NMDARs and the other one based on the activation of mGluRs.

Brief Dark Exposure Reduces Tonic Inhibition in Visual Cortex.

Tonic inhibition mediated by extrasynaptic GABA(A) receptors (GABARs) sensing ambient levels of GABA can profoundly alter the membrane input resistance to affect cellular excitability. Therefore, regulation of tonic inhibition is an attractive mechanism to control the levels of cortical firing. In cortical pyramidal cells, tonic inhibition is regulated by age and several neurotransmitters and is affected by stroke and epilepsy. However, the possible role of sensory experience has not been examined. Here, we report that a brief 2-day exposure to dark reduces by 1/3 the inhibitory tonic conductance recorded in layer II/III pyramidal cells of the mouse juvenile (postnatal day 12-27) visual cortex. In these cells, tonic inhibition is carried primarily by GABARs containing the δ subunit. Consistently, the dark exposure reduction in conductance was associated with a reduction in δ subunit levels, which were not affected in control frontal cortex. We propose that a deprivation-induced reduction in tonic inhibition might serve a homeostatic function by increasing the firing levels of cells in deprived cortical circuits.

Defective Age-Dependent Metaplasticity in a Mouse Model of Alzheimer's Disease.

Much of the molecular understanding of synaptic pathology in Alzheimer's disease (AD) comes from studies of various mouse models that express familial AD (FAD)-linked mutations, often in combinations. Most studies compare the absolute magnitudes of long-term potentiation (LTP) and long-term depression (LTD) to assess deficits in bidirectional synaptic plasticity accompanying FAD-linked mutations. However, LTP and LTD are not static, but their induction threshold is adjusted by overall neural activity via metaplasticity. Hence LTP/LTD changes in AD mouse models may reflect defects in metaplasticity processes. To determine this, we examined the LTP/LTD induction threshold in APPswe;PS1ΔE9 transgenic (Tg) mice across two different ages. We found that in young Tg mice (1 month), LTP is enhanced at the expense of LTD, but in adults (6 months), the phenotype is reversed to promote LTD and reduce LTP, compared to age-matched wild-type (WT) littermates. The apparent opposite phenotype across age was due to an initial offset in the induction threshold to favor LTP and the inability to undergo developmental metaplasticity in Tg mice. In WTs, the synaptic modification threshold decreased over development to favor LTP and diminish LTD in adults. However, in Tg mice, the magnitudes of LTP and LTD stayed constant across development. The initial offset in LTP/LTD threshold in young Tg mice did not accompany changes in the LTP/LTD induction mechanisms, but altered AMPA receptor phosphorylation and appearance of Ca(2+)-permeable AMPA receptors. We propose that the main synaptic defect in AD mouse models is due to their inability to undergo developmental metaplasticity. SIGNIFICANCE STATEMENT: This work offers a new insight that metaplasticity defects are central to synaptic dysfunctions seen in AD mouse models. In particular, we demonstrate that the apparent differences in LTP/LTD magnitude seen across ages in AD transgenic mouse models reflect the inability to undergo a normal developmental shift in metaplasticity.

Associative Hebbian synaptic plasticity in primate visual cortex.

In primates, the functional connectivity of adult primary visual cortex is susceptible to be modified by sensory training during perceptual learning. It is widely held that this type of neural plasticity might involve mechanisms like long-term potentiation (LTP) and long-term depression (LTD). NMDAR-dependent forms of LTP and LTD are particularly attractive because in rodents they can be induced in a Hebbian manner by near coincidental presynaptic and postsynaptic firing, in a paradigm termed spike timing-dependent plasticity (STDP). These fundamental properties of LTP and LTD, Hebbian induction and NMDAR dependence, have not been examined in primate cortex. Here we demonstrate these properties in the primary visual cortex of the rhesus macaque (Macaca mulatta), and also show that, like in rodents, STDP is gated by neuromodulators. These findings indicate that the cellular principles governing cortical plasticity are conserved across mammalian species, further validating the use of rodents as a model system.

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-ß (Aß) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aß oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aß oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aß oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated.

Adrenergic gating of Hebbian spike-timing-dependent plasticity in cortical interneurons.

In pyramidal cells, the induction of spike-dependent plasticity (STDP) follows a simple Hebbian rule in which the order of presynaptic and postsynaptic firing dictates the induction of LTP or LTD. In contrast, cortical fast spiking (FS) interneurons, which control the rate and timing of pyramidal cell firing, reportedly express timing-dependent LTD, but not timing-dependent LTP. Because a mismatch in STDP rules could impact the maintenance of the excitation/inhibition balance, we examined the neuromodulation of STDP in FS cells of mouse visual cortex. We found that stimulation of adrenergic receptors enables the induction of Hebbian bidirectional STDP in FS cells in a manner consistent with a pull-push mechanism previously characterized in pyramidal cells. However, in pyramidal cells, STDP induction depends on NMDA receptors, whereas in FS cells it depends on mGluR5 receptors. We propose that neuromodulators control the polarity of STDP in different synapses in the same manner, and independently of the induction mechanism, by acting downstream in the plasticity cascade. By doing so, neuromodulators may allow coordinated plastic changes in FS and pyramidal cells.

Integrity of mGluR-LTD in the associative/commissural inputs to CA3 correlates with successful aging in rats.

The impact of aging on cognitive capabilities varies among individuals ranging from significant impairment to preservation of function on par with younger adults. Research on the neural basis for age-related memory decline has focused primarily on the CA1 region of the hippocampus. However, recent studies in elderly human and rodents indicate that individual differences in cognitive aging are more strongly tied to functional alterations in CA3 circuits. To examine synaptic plasticity in the CA3 region, we used aged rats behaviorally characterized in a hippocampal-dependent task to evaluate the status of long-term potentiation and long-term depression (LTP and LTD) in the associative/commissural pathway (A/C → CA3), which provides the majority of excitatory input to CA3 pyramidal neurons. We found that, unlike in CA1 synapses, in A/C → CA3 LTP is minimally affected by age. However, two forms of LTD, involving NMDA and metabotropic glutamate receptors (mGluR), are both greatly reduced in age-impaired rats. Age-unimpaired rats, in contrast, had intact mGluR LTD. These findings indicate that the integrity of mGluR-LTD at A/C → CA3 inputs may play a crucial role in maintaining the performance of CA3 circuitry in aging.

A tetra(ethylene glycol) derivative of benzothiazole aniline enhances Ras-mediated spinogenesis.

The tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, is a novel amyloid-binding small molecule that can penetrate the blood-brain barrier and protect cells from Aß-induced toxicity. However, the effects of Aß-targeting molecules on other cellular processes, including those that modulate synaptic plasticity, remain unknown. We report here that BTA-EG4 decreases Aß levels, alters cell surface expression of amyloid precursor protein (APP), and improves memory in wild-type mice. Interestingly, the BTA-EG4-mediated behavioral improvement is not correlated with LTP, but with increased spinogenesis. The higher dendritic spine density reflects an increase in the number of functional synapses as determined by increased miniature EPSC (mEPSC) frequency without changes in presynaptic parameters or postsynaptic mEPSC amplitude. Additionally, BTA-EG4 requires APP to regulate dendritic spine density through a Ras signaling-dependent mechanism. Thus, BTA-EG4 may provide broad therapeutic benefits for improving neuronal and cognitive function, and may have implications in neurodegenerative disease therapy.

SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity.

SynGAP is an abundant synaptic GTPase-activating protein (GAP) critical for synaptic plasticity, learning, memory, and cognition. Mutations in SYNGAP1 in humans result in intellectual disability, autistic-like behaviors, and epilepsy. Heterozygous Syngap1-knockout mice display deficits in synaptic plasticity, learning, and memory and exhibit seizures. It is unclear whether SynGAP imparts structural properties at synapses independently of its GAP activity. Here, we report that inactivating mutations within the GAP domain do not inhibit synaptic plasticity or cause behavioral deficits. Instead, SynGAP modulates synaptic strength by physically competing with the AMPA-receptor-TARP excitatory receptor complex in the formation of molecular condensates with synaptic scaffolding proteins. These results have major implications for developing therapeutic treatments for SYNGAP1-related neurodevelopmental disorders.