Biology subjects

Turrigiano, G.

Publications and source records attributed to Turrigiano, G..

6 recordsLinked to original sources

bioRxiv2025

Learning-Associated Flexibility of Cortical Taste Coding Is Impaired in Shank3 Knockout Mice

The ability to update the valence of sensory perception to influence behavior is crucial for survival. A common phenotype in autism spectrum disorders (ASDs) is defects in sensory processing, but whether these defects impair flexible sensory encoding is largely unexplored. In particular, how genetic risk factors such as Shank3 deletion affect the adaptability of cortical taste processing and downstream behavior is unknown. To address this gap, we performed two-photon calcium imaging during a conditioned taste aversion (CTA) learning paradigm, an ethologically relevant form of associative learning that depends on taste processing in the gustatory cortex (GC), to examine how Shank3 knockout alters taste-related neuronal activity in GC and influences CTA learning. We found that GC neurons in Shank3 knockout mice exhibited reduced stimulus-evoked suppression and increased trial-to-trial correlated variability during the acquisition of CTA memory. These activity changes, which likely reduced signal-to- noise ratio in GC, were associated with slower CTA acquisition in knockout mice. In both genotypes, CTA learning enhanced, while subsequent extinction reduced, taste discriminability in GC, and both extinction and the associated reduction in discriminability were faster in knockout than in wild-type mice. Together, these results show that Shank3 loss is associated with destabilized cortical activity dynamics in GC, which may contribute to inefficient encoding and maintenance of learned taste aversion. These findings show that loss of Shank3 compromises the ability of animals to update behavior to incorporate negative outcomes, and suggest this loss of flexibility may be an important feature of monogenic ASDs.

neuroscience↗

bioRxiv2025

Activity deprivation modulates the Shank3/Homer1/mGluR5 signaling pathway to enable synaptic upscaling

Shank3 is an autism spectrum disorder-associated postsynaptic scaffold protein that links glutamate receptors to trafficking and signaling networks within the postsynaptic density. Shank3 is required for synaptic scaling (Tatavarty et al., 2020), a form of homeostatic plasticity that bidirectionally modulates post-synaptic strength in the right direction to stabilize neuronal activity. Shank3 undergoes activity-dependent phosphorylation/dephosphorylation at S1586/S1615, and dephosphorylation at these sites is critical for enabling synaptic upscaling (Wu et al., 2022). Here, we probe the molecular machinery downstream of Shank3 dephosphorylation that allows for synaptic upscaling. We first show that a phosphomimetic mutant of Shank3 has reduced binding ability and interaction with long-form Homer1, a postsynaptic protein also crucial for scaling, and a known binding partner of Shank3. Since metabotropic glutamate receptor 5 (mGluR5) has been shown to associate with Shank3 through long-form Homer1, we manipulated mGluR5 signaling with either noncompetitive or competitive inhibitors and found that only competitive inhibition (which targets agonist-dependent signaling) impairs synaptic upscaling. Further, we found that mGluR5 activation rescues synaptic upscaling in the presence of phosphomimetic Shank3, thus is downstream of Shank3 phosphorylation. Finally, we identify necessary signaling pathways downstream of group I mGluR. Taken together, these data show that activity-dependent dephosphorylation of Shank3 remodels the Shank3/Homer1/mGluR signaling pathway to favor agonist-dependent mGluR signaling, which is necessary to enable synaptic upscaling. More broadly, because downscaling depends on agonist-independent mGluR5 signaling, these findings demonstrate that synaptic up and downscaling rely on distinct functional configurations of the same signaling elements. SIGNIFICANCE STATEMENTSynaptic scaling is a bidirectional, homeostatic form of synaptic plasticity that allows neural circuits to maintain stable function in the face of experience-dependent or developmental perturbations. Synaptic scaling up requires dephosphorylation of the Autism Spectrum Disorder (ASD)-associated synaptic scaffold protein Shank3, but how this dephosphorylation event enables scaling up was unknown. Here we show that dephosphorylation of Shank3 rearranges interactions between synaptic proteins to drive agonist-dependent signaling through metabotropic glutamate receptors (mGluRs), and that this signaling is necessary for scaling up. These findings show that altered mGluR signaling is downstream of Shank3 during homeostatic plasticity, and raise the possibility that some human Shankopathies impair signaling through this important signaling pathway.

neuroscience↗

bioRxiv2023

Cholinergic Modulation is Necessary for Upward Firing Rate Homeostasis in Rodent Visual Cortex

Bidirectional homeostatic plasticity allows neurons and circuits to maintain stable firing in the face of developmental or learning-induced perturbations. In primary visual cortex (V1), upward firing rate homeostasis (FRH) only occurs during active wake (AW) and downward during sleep, but how this behavioral state-dependent gating is accomplished is unknown. Here we focus on how AW enables upward FRH in V1 of juvenile Long Evans rats. A major difference between quiet wake (QW) when upward FRH is absent, and AW when it is present, is increased cholinergic (ACh) tone; we therefore chemogenetically inhibited V1-projecting basal forebrain cholinergic (BF ACh) neurons while inducing upward FRH using visual deprivation, and found that upward FRH was completely abolished. Next, we examined the impact on synaptic scaling and intrinsic excitability, two important cellular targets of homeostatic regulation. BF ACh inhibition impaired synaptic scaling up, and dramatically decreased the intrinsic excitability of activity-deprived V1 pyramidal neurons, consistent with the block of upward FRH. Interestingly, knock down of the highly abundant M1 ACh receptor in V1 failed to phenocopy the effects of decreased BF ACh activity on intrinsic excitability, suggesting either that BF ACh activity acts through a different receptor within V1, or acts indirectly via other brain regions or cell types. Together, our results show that BF ACh modulation is a key enabler of upward homeostatic plasticity, and more broadly suggest that neuromodulatory tone is a critical factor that segregates upward and downward homeostatic plasticity into distinct behavioral states. SIGNIFICANCE STATEMENTHebbian, positive feedback-based and homeostatic, negative feedback-based plasticity mechanisms are necessary to maintain the functionality of flexible yet stable complex neuronal circuits. Growing evidence suggests a role for behavioral state in temporally segregating these opposing plasticity mechanisms, but how behavioral states enact this gating remains unknown. Here, we tested the role of acetylcholine (ACh), a widespread neuromodulator largely released during active wake, in the regulation of upward homeostatic plasticity. We found that ACh modulation is indeed necessary for the expression of active wake-gated upward firing rate homeostasis, likely due to its role in maintaining intrinsic excitability of cortical pyramidal neurons. Our results suggest potential mechanisms by which neuromodulatory tone may enable behavioral state gating of homeostatic plasticity.

neuroscience↗

bioRxiv2021

Developmental Regulation of Homeostatic Plasticity in Mouse Primary Visual Cortex

Homeostatic plasticity maintains network stability by adjusting excitation, inhibition, or the intrinsic excitability of neurons, but the developmental regulation and coordination of these distinct forms of homeostatic plasticity remains poorly understood. A major contributor to this information gap is the lack of a uniform paradigm for chronically manipulating activity at different developmental stages. To overcome this limitation, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to directly suppress neuronal activity in layer (L) 2/3 of mouse primary visual cortex (V1) at two important developmental timepoints: the classic visual system critical period (CP, P24-29), and adulthood (P45-55). We show that 24 hours of DREADD-mediated activity suppression simultaneously induces excitatory synaptic scaling up and intrinsic homeostatic plasticity in L2/3 pyramidal neurons during the CP, consistent with previous observations using prolonged visual deprivation. Importantly, manipulations known to block these forms of homeostatic plasticity when induced pharmacologically or via visual deprivation also prevented DREADD-induced homeostatic plasticity. We next used the same paradigm to suppress activity in adult animals. Surprisingly, while excitatory synaptic scaling persisted into adulthood, intrinsic homeostatic plasticity was completely absent. Finally, we found that homeostatic changes in quantal inhibitory input onto L2/3 pyramidal neurons were absent during the CP but present in adults. Thus, the same population of neurons can express distinct sets of homeostatic plasticity mechanisms at different development stages. Our findings suggest that homeostatic forms of plasticity can be recruited in a modular manner according to the evolving needs of a developing neural circuit. Significance statementDeveloping brain circuits are subject to dramatic changes in inputs that could destabilize activity if left uncompensated. This compensation is achieved through a set of homeostatic plasticity mechanisms that provide slow, negative feedback adjustments to excitability. Given that circuits are subject to very different destabilizing forces during distinct developmental stages, the forms of homeostatic plasticity present in the network must be tuned to these evolving needs. Here we developed a method to induce comparable homeostatic compensation during distinct developmental windows, and found that neurons in the juvenile and mature brain engage strikingly different forms of homeostatic plasticity. Thus, homeostatic mechanisms can be recruited in a modular manner according to the developmental needs of the circuit.

neuroscience↗

bioRxiv2020

Homeostatic Synaptic Scaling Establishes the Specificity of an Associative Memory

Accurate memory formation has been hypothesized to depend on both rapid Hebbian plasticity for initial encoding, and slower homeostatic mechanisms that prevent runaway excitation and subsequent loss of memory specificity. Here, we tested the role of synaptic scaling in shaping the specificity of conditioned taste aversion (CTA) memory, a Hebbian plasticity-dependent form of associative learning. We found that CTA memory initially generalized to non-conditioned tastants (generalized aversion), becoming specific to the conditioned tastant only over the course of many hours. Blocking synaptic scaling in the gustatory cortex (GC) prolonged the duration of the initial generalized aversion and enhanced the persistence of synaptic strength increases observed after CTA. Taken together, these findings demonstrate that synaptic scaling is important for sculpting the specificity of an associative memory and suggest that the relative strengths of Hebbian and homeostatic plasticity can modulate the balance between stable memory formation and generalization.

neuroscience↗

bioRxiv2019

Activity labeling in vivo using CaMPARI2 reveals electrophysiological differences between neurons with high and low firing rate set points

Individual excitatory neurons in visual cortex (V1) display remarkably stable mean firing rates over many days, even though these rates can differ by several orders of magnitude between neurons. When perturbed, each neurons firing rate is slowly regulated back to its pre-perturbation level, demonstrating that neurons maintain their mean firing rate around an individual firing rate set point (FRSP). To better understand the mechanisms that neurons within a single cell type use to maintain different FRSPs in vivo, we implemented a novel method of activity labeling that uses CaMPARI2, a fluorescent protein that undergoes Ca2+- and UV-dependent green-to-red photoconversion, to permanently label neurons in freely behaving mice based on their firing rates. We found that immediate early gene (IEG) expression was correlated with CaMPARI2 red/green ratio following an activity stimulation paradigm, and that neurons with greater photoconversion in vivo tended to have a higher firing rate ex vivo. In layer 4 (L4) pyramidal neurons in mouse monocular V1, which comprise a single transcriptional cell type, we found that high activity neurons had a left-shifted F-I curve, lower rheobase current, and decreased spike adaptation index relative to low activity neurons, demonstrating increased intrinsic excitability. Surprisingly, we found no difference in total excitatory or inhibitory synaptic current or in E/I ratio between high and low activity neurons. Thus, within a single cell type differences in intrinsic excitability and spike frequency adaptation can contribute to divergent activity set points. These results reveal that E/I ratio plays only a minor role in determining the firing rate set point of L4 pyramidal neurons, while intrinsic excitability is an important factor.

neuroscience↗