The shift in ocular dominance (OD) of binocular neurons induced by monocular deprivation is the canonical model of synaptic plasticity confined to a postnatal critical period. Developmental constraints on this plasticity not only lend stability to the mature visual cortical circuitry but also impede the ability to recover from amblyopia beyond an early window. Advances with mouse models utilizing the power of molecular, genetic, and imaging tools are beginning to unravel the circuit, cellular, and molecular mechanisms controlling the onset and closure of the critical periods of plasticity in the primary visual cortex (V1). Emerging evidence suggests that mechanisms enabling plasticity in juveniles are not simply lost with age but rather that plasticity is actively constrained by the developmental up-regulation of molecular ‘brakes’. Lifting these brakes enhances plasticity in the adult visual cortex, and can be harnessed to promote recovery from amblyopia. The reactivation of plasticity by experimental manipulations has revised the idea that robust OD plasticity is limited to early postnatal development. Here, we discuss recent insights into the neurobiology of the initiation and termination of critical periods and how our increasingly mechanistic understanding of these processes can be leveraged toward improved clinical treatment of adult amblyopia.

Glial−neuronal interactions are crucial processes in neuromodulation and synaptic plasticity. The neuregulin 1 family of growth and differentiation factors have been implicated as bidirectional signaling molecules that are involved in mediating some of these interactions. We have shown previously that neuregulin 1 expression is regulated by the gonadal hormones progesterone and 17β-estradiol in the CNS, which might represent a novel, indirect mechanism of the neuromodulatory actions of these gonadal hormones. In the present study, we sought to determine the effects of progesterone and 17β-estradiol on neuregulin 1 expression in rat cortical astrocytes and neurons in vitro. We observed that progesterone increased the expression of neuregulin 1 mRNA and protein in a dose-dependent manner in cultured astrocytes, which was blocked by the progesterone receptor antagonist RU-486. In contrast, 17β-estradiol did not increase either neuregulin 1 mRNA or protein in astrocytes. We observed no effect of either progesterone or 17β-estradiol on neuregulin 1 mRNA and protein in rat cortical neurons in vitro. Finally, we observed that treatment of cortical neurons with recombinant NRG1-β1 caused PSD-95 to localize in puncta similar to that observed following treatment with astrocyte-conditioned medium. These results demonstrate that progesterone regulates neuregulin 1 expression, principally in astrocytes. This might represent a novel mechanism of progesterone-mediated modulation of neurotransmission through the regulation of astrocyte-derived neuregulin 1.

Thalamic afferents and efferents primarily use the neurotransmitter glutamate, which acts through a variety of ionotropic (NMDA, AMPA, kainate) and metabotropic receptors. The NMDAR is composed of multiple subunits, NR1 and NR2A-D. The obligatory NRl subunit is expressed as one of eight isoforms, due to the alternative splicing of exons 5, 21, and 22. Each NRl splice variant is functionally distinct. For instance, alternative splicing of exons 21 and 22 renders two C-terminal variants, which differentially associate with NR2 subunits and intracellular molecules such the PSD-95 family of proteins. These PSD proteins play a pivotal role in NMDAR function by linking NMDARs to the cytoskeleton and downstream signal-transducing enzymes that can directly modulate NMDAR function and/or promote NMDAR-associated intracellular events.

Previous work reported that NRl is by far the most abundant NMDAR subunit expressed in the primate thalamus. In the current study, we extend these findings first by determining which NRl isoforms are predominantly expressed in the thalamus. Secondly, we characterize the expression of the NMDAR-associated PSD molecules, such as PSD-95, in the thalamus. Using in situ hybridization, we examined expression of the transcripts encoding NRl isoforms containing exons 5, 21, or 22, and transcripts encoding a set of the most well-characterized NMDAR-associated PSD proteins (NF-L, PSD93, PSD95, SAP102, and Yotiao). NRl exon 22-containing isoforms are the most abundant subunit transcripts, accounting for 40–50% of the NRl isoforms expressed in most thalamic nuclei. We also found that NF-L is by far the most abundant PSD protein expressed in the thalamus, followed by PSD-95, which is moderately and heterogeneously expressed. SAP102 and PSD-93 were expressed at moderate to low levels, with negligible amounts of Yotiao transcript expression. The PSD-95 family of molecules are critical for NMDAR function in the cell, and this study is the first to provide a detailed description of the expression of these molecules in primate thalamus. Our results demonstrate that NRl splice variants and associated PSD proteins are heterogeneously expressed across the thalamus, which is likely related to the intracellular events that occur in different thalamic nuclei.