BACKGROUND Fragile X Syndrome (FXS) is the most common type of mental retardation attributable to a single-gene mutation. It is caused by FMR1 gene silencing and the consequent loss of its protein product, Fragile X Mental Retardation Protein (FMRP). Fmr1 global knock out (KO) mice recapitulate many behavioral and synaptic phenotypes associated with FXS. Abundant evidence suggests that astrocytes are important contributors to neurological diseases. This study investigates astrocytic contributions to the progression of synaptic abnormalities and learning impairments associated with FXS. METHODS Taking advantage of the Cre-lox system, we generated and characterized mice in which FMRP is selectively deleted or exclusively expressed in astrocytes. We performed in vivo two-photon imaging to track spine dynamics/morphology along dendrites of neurons in the motor cortex and examined associated behavioral defects. RESULTS We found that adult astrocyte-specific Fmr1 KO mice displayed an increased spine density in the motor cortex and impaired motor-skill learning. The learning defect coincided with a lack of enhanced spine dynamics in the motor cortex that normally occurs in response to motor skill acquisition. While spine density was normal at one month of age in astrocyte-specific Fmr1 KO mice, new spines formed at an elevated rate. Furthermore, expression of FMRP only in astrocytes was insufficient to rescue most spine or behavioral defects. CONCLUSIONS Our work suggests a joint astrocytic-neuronal contribution to FXS pathogenesis and reveals that heightened spine formation during adolescence precedes the overabundance of spines and behavioral defects found in adult Fmr1 KO mice.
Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790–8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68+ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.
Corticothalamic (CT) feedback plays an important role in regulating the sensory information that the cortex receives. Within the somatosensory cortex layer VI originates the feedback to the ventral posterior medial (VPM) nucleus of the thalamus, which in turn receives sensory information from the contralateral whiskers. We examined the physiology and morphology of CT neurons in rat somatosensory cortex, focusing on the physiological characteristics of the monosynaptic inputs that they receive from the thalamus. To identify CT neurons, rhodamine microspheres were injected into VPM and allowed to retrogradely transport to the soma of CT neurons. Thalamocortical slices were prepared at least 3 days post injection. Whole-cell recordings from labeled CT cells in layer VI demonstrated that they are regular spiking neurons and exhibit little spike frequency adaption. Two anatomical classes were identified based on their apical dendrites that either terminated by layer V (compact cells) or layer IV (elaborate cells). Thalamic inputs onto identified CT-VPM neurons demonstrated paired pulse depression over a wide frequency range (2-20 Hz). Stimulus trains also resulted in significant synaptic depression above 10 Hz. Our results suggest that thalamic inputs differentially impact CT-VPM neurons in layer VI. This characteristic may allow them to differentiate a wide range of stimulation frequencies which in turn further tune the feedback signals to the thalamus.
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