Biology subjects

Heynen, A. J.

Publications and source records attributed to Heynen, A. J..

4 recordsLinked to original sources

bioRxiv2026

Tuning metaplasticity in the adult visual cortex using flickering light

Synaptic connections in the brain are refined by sensory experience during an early postnatal critical period, but by adulthood synaptic connectivity is resistant to further changes. A consequence of lost plasticity is limited recovery from brain injury, disease, and adverse sensory experience. Thus, there is great interest in treatments that can promote synaptic modifications in the adult brain. In a wide variety of contexts, it has been established that the qualities of synaptic plasticity are not fixed but rather vary depending on the recent history of cellular or synaptic activity1. This plasticity of plasticity, or metaplasticity2 explains why temporary manipulations of brain activity (e.g., by drugs3, transcranial stimulation4, or sensory deprivation5) can set the stage for subsequent, potentially therapeutic, long-lasting synaptic modifications6. Here we tested the hypothesis that plasticity in the adult mouse visual cortex is influenced by prior exposure to temporally modulated light and discovered that different flicker frequencies have qualitatively different effects. Exposure to 60 Hz stimulation increased microglia density, depleted perineuronal nets (PNNs), and restored ocular dominance plasticity in response to brief monocular deprivation (MD). Exposure to 40 Hz flicker also enabled ocular dominance plasticity, but it did so in a distinct way and without PNN remodeling. A key distinction is that unlike 60 Hz flicker, which enabled depression of synaptic strength by MD, 40 Hz flicker promoted synaptic strengthening. Indeed, we found that 40 Hz flicker primed a rapid and robust recovery from the effects of long-term MD that failed to occur after 60 Hz flicker. Thus, metaplasticity can be non-invasively "tuned" by light flickering at different frequencies to encourage different forms of synaptic plasticity in the cerebral cortex, including modifications that enable recovery of function.

neuroscience↗

bioRxiv2024

Non-ionotropic signaling through the NMDA receptor GluN2B carboxy terminal domain drives morphological plasticity of dendritic spines and reverses fragile X phenotypes in mouse hippocampus

It is well known that activation of NMDA receptors can trigger long-term synaptic depression (LTD) and that a morphological correlate of this functional plasticity is spine retraction and elimination. Recent studies have led to the surprising conclusion that NMDA-induced spine shrinkage proceeds independently of ion flux and requires the initiation of de novo protein synthesis, highlighting an unappreciated contribution of mRNA translation to non-ionotropic NMDAR signaling. Here we used NMDA-induced spine shrinkage in slices of mouse hippocampus as a readout to investigate this novel modality of synaptic transmission. By using selective pharmacological and genetic tools, we find that structural plasticity is dependent on the ligand binding domain (LBD) of GluN2B-containing NMDA receptors and that metabotropic signaling occurs via the GluN2B carboxyterminal domain (CTD). Disruption of signaling by replacing the GluN2B CTD with the GluN2A CTD leads to increased spine density, dysregulated basal protein synthesis, and epileptiform activity in area CA3 reminiscent of phenotypes observed in the Fmr1-/y model of fragile X syndrome. By crossing the Fmr1-/y mice with animals in which the GluN2A CTD has been replaced with the GluN2B CTD, we observe a correction of these core fragile X phenotypes. These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for treatment of fragile X and related causes of intellectual disability and autism.

neuroscience↗

bioRxiv2022

The Impact of Brief Monocular Retinal Inactivation on the Central Visual System During Postnatal Development

During a critical period of postnatal life, monocular deprivation (MD) of kittens by eyelid closure reduces the size of neurons in layers of the dorsal lateral geniculate nucleus (dLGN) connected to the deprived eye, and shifts cortical ocular dominance in favor of the non-deprived eye, modeling deprivation amblyopia in humans. Following long-term MD, temporary retinal inactivation of the non-deprived eye with microinjection of tetrodotoxin can promote superior recovery from MD, and at older ages, in comparison to conventional occlusion therapy. This suggests that monocular inactivation (MI) is a more potent approach to producing neural plasticity than occlusion. In the current study we assessed the modification of neuron size in the dLGN as a means of measuring the impact of a brief period of MI imposed at different ages during postnatal development. The biggest impact of inactivation was observed when it occurred at the peak of the critical period for ocular dominance plasticity. The effect of MI was evident in both the binocular and monocular segments of the dLGN, distinguishing it from MD that produces changes only within the binocular segment. With increasing age, the capacity for inactivation to alter postsynaptic cell size diminished but was still significant beyond the classic critical period. In comparison to MD, inactivation consistently produced effects that were about double in magnitude, and inactivation exhibited efficacy to produce neural modifications at older ages than MD. Notwithstanding the large neural alterations precipitated by inactivation, its anatomical effects were remediated with a short period of binocular visual experience, and vision through the previously inactivated eye fully recovered after washout of TTX. Our results demonstrate that MI is a potent means of modifying the visual pathway, and does so beyond the age at which occlusion is effective. The magnitude and longevity of inactivation to evoke neural modification highlights its potential to ameliorate disorders of the visual system such as amblyopia.

neuroscience↗

bioRxiv2021

mGluR5 Negative Modulators for Fragile X: Resistance and Persistence

Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance ("tolerance") after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3 (GSK3), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.

neuroscience↗