Age-related changes in inhibitory neurotransmission in sensory cortex may underlie deficits in sensory function. Perineuronal nets (PNNs) are extracellular matrix components that ensheath some inhibitory neurons, particularly parvalbumin positive (PV+) interneurons. PNNs may protect PV+ cells from oxidative stress and help establish their rapid spiking properties. Although PNN expression has been well characterized during development, possible changes in aging sensory cortex have not been investigated. Here we tested the hypothesis that PNN+, PV+ and PV/PNN co-localized cell densities decline with age in the primary auditory cortex (A1). This hypothesis was tested using immunohistochemistry in two strains of mice (C57BL/6 and CBA/CaJ) with different susceptibility to age-related hearing loss and at three different age ranges (1–3, 6–8 and 14–24 months old). We report that PNN+ and PV/PNN co-localized cell densities decline significantly with age in A1 in both mouse strains. In the PNN+ cells that remain in the old group, the intensity of PNN staining is reduced in the C57 strain, but not the CBA strain. PV+ cell density also declines only in the C57, but not the CBA, mouse suggesting a potential exacerbation of age-effects by hearing loss in the PV/PNN system. Taken together, these data suggest that PNN deterioration may be a key component of altered inhibition in the aging sensory cortex, that may lead to altered synaptic function, susceptibility to oxidative stress and processing deficits.

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Fragile X syndrome (FXS) is a leading genetic cause of autism-like symptoms that include sensory hypersensitivity and cortical hyperexcitability. Recent observations in humans and Fmr1 knockout (KO) animal models of FXS suggest abnormal GABAergic signaling. As most studies focused on neuron-centered mechanisms, astrocytes contribution to abnormal inhibition is largely unknown. Here we propose a non-neuronal mechanism of abnormal inhibitory circuit development in FXS. Astrocyte-specific deletion of Fmr1 during postnatal period leads to increased astrocytic GABA levels, but negatively impacts synaptic GABAA receptors and parvalbumin (PV) cell development. Developmental deletion of Fmr1 from astrocytes also affects communications between excitatory neurons and PV cells, impairing sound-evoked gamma synchronization in the cortex, while enhancing baseline and on-going sound-evoked EEG power, and leading to increased locomotor activity and altered social behaviors in adult mice. These results demonstrate a profound role of astrocytic FMRP in the development of inhibitory circuits and shaping normal inhibitory responses.

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