Perineuronal nets (PNNs) are aggregates of extracellular matrix that form structures surrounding a subset of GABAergic interneurons. The staining intensity of PNNs appears to be related to plasticity. Environmental enrichment (EE) influences plasticity during adulthood: EE decreases the rewarding effects of drugs of abuse and diminishes both drug- and sucrose-seeking behavior. We determined the impact of EE on PNN intensity in the medial prefrontal cortex (mPFC) in rats trained to self-administer sucrose. We examined the number and intensity of PNNs within the prelimbic (PL), infralimbic (IL), and orbitofrontal (OF) regions of the mPFC of adult Long-Evans rats that were trained for sucrose self-administration followed by acute or chronic EE during abstinence and a cue-induced reinstatement test. Rats exposed to EE prior to a cue-induced reinstatement of sucrose seeking had an increase in PNN staining compared with rats in standard housing. Conversely, naïve rats given 1 day of EE had a decrease in PNN intensity in the PL, no change in the IL, and an increase in the OF. Our findings demonstrate that EE increases PNN intensity in the mPFC after sucrose training, suggesting that training enhances the ability of EE to increase PNN intensity. We further demonstrate an interaction between time of abstinence, duration of EE exposure, and cue-induced reinstatement. Our results suggest that increased PNN intensity after EE may alter the excitatory/inhibitory balance of mPFC neurons such that rats are less responsive to a sucrose cue.

Lowe syndrome (LS) is a rare genetic disorder caused by loss of function mutations in the X-linked gene, OCRL, which codes for inositol polyphosphate 5-phosphatase. LS is characterized by the triad of congenital cataracts, neurodevelopmental impairment (primarily intellectual and developmental disabilities [IDD]), and renal proximal tubular dysfunction. Studies carried out over the years have shown that hypomorphic mutations in OCRL adversely affect endosome recycling and actin polymerization in kidney cells and patient-derived fibroblasts. The renal problem has been traced to an impaired recycling of megalin, a multi-ligand receptor that plays a key role in the reuptake of lipoproteins, amino acids, vitamin-binding proteins, and hormones. However, the neurodevelopmental aspects of the disorder have been difficult to study because the mouse knockout (KO) model does not display LS-related phenotypes. Fortunately, the discovery of induced pluripotent stem (iPS) cells has provided an opportunity to grow patient-specific neurons, which can be used to model neurodevelopmental disorders in vitro, as demonstrated in the many studies that have been published in the past few years in autism spectrum disorders (ASD), schizophrenia (SZ), bipolar disorder (BD), and IDD.

Jansen de Vries Syndrome (JdVS) is a rare neurodevelopmental disorder (NDD) caused by gain-of-function (GOF) truncating mutations in PPM1D exons 5 or 6. PPM1D is a serine/threonine phosphatase that plays an important role in the DNA damage response (DDR) by negatively regulating TP53 (P53). JdVS-associated mutations lead to the formation of a truncated PPM1D protein that retains catalytic activity and has a GOF effect because of reduced degradation. Somatic PPM1D exons 5 and 6 truncating mutations are well-established factors in a number of cancers, due to excessive dephosphorylation and reduced function of P53 and other substrates involved in DDR. Children with JdVS have a variety of neurodevelopmental, psychiatric, and physical problems. In addition, a small fraction has acute neuropsychiatric decompensation apparently triggered by infection or severe non-infectious environmental stress factors.

Environmental enrichment (EE) reduces drug and sucrose cue-reactivity in rats. In a previous study we reported that 1 month of EE (large cage, toys, and social cohorts) significantly reduced sucrose cue-reactivity. In the present study, we examined whether overnight (22 h) EE would be as effective. We also examined whether social enrichment (SE), enrichment alone (SoloEE), or exposure to an alternative environment (AEnv) might account for the EE effect. Rats self-administered 10% sucrose (.2 mL/delivery) in 10 daily 2-h sessions. Sucrose delivery was accompanied by a tone+light cue. Rats were then exposed to enrichment or alternative environment conditions overnight (acute) or for 29 days (chronic). Sucrose cue-reactivity was measured after this period of forced abstinence in a session identical to training, but no sucrose was delivered with the cue. All acute conditions markedly reduced sucrose cue-reactivity after 1 day of forced abstinence compared to single-housed rats in standard vivarium housing (CON). Sucrose consumption was also significantly reduced in all groups but SoloEE in a next-day test. All acute conditions but SE significantly reduced sucrose cue-reactivity when administered just prior to Day 30 of forced abstinence; all reduced sucrose consumption in a next-day test. All chronic conditions except for SE and AEnv significantly reduced sucrose cue-reactivity on the Day 30 test and sucrose consumption in a next day test. For both acute and chronic comparisons, EE manipulations were the most effective at reducing sucrose cue-reactivity and consumption. SoloEE and EE were equally effective at reducing sucrose cue-reactivity and similarly effective at reducing sucrose consumption. This indicates that social interaction is not a necessary condition for reducing sucrose-motivated behaviors. These results may be useful in the development of anti-relapse strategies for drug and food addictions.

Lowe syndrome (LS) is caused by loss-of-function mutations in the X-linked gene OCRL, which codes for an inositol polyphosphate 5-phosphatase that plays a key role in endosome recycling, clathrin-coated pit formation, and actin polymerization. It is characterized by congenital cataracts, intellectual and developmental disability, and renal proximal tubular dysfunction. Patients are also at high risk for developing glaucoma and seizures. We recently developed induced pluripotent stem cell (iPSC) lines from three patients with LS who have hypomorphic variants affecting the 3' end of the gene, and their neurotypical brothers to serve as controls.