Hyperconnectivity and Slow Synapses during Early Development of Medial Prefrontal Cortex in a Mouse Model for Mental Retardation and Autism

Abstract

Neuronal theories of neurodevelopmental disorders (NDDs) of autism and mental retardation propose that abnormal connectivity underlies deficits in attentional processing. We tested this theory by studying unitary synaptic connections between layer 5 pyramidal neurons within medial prefrontal cortex (mPFC) networks in the Fmr1-KO mouse model for mental retardation and autism. In line with predictions from neurocognitive theory, we found that neighboring pyramidal neurons were hyperconnected during a critical period in early mPFC development. Surprisingly, excitatory synaptic connections between Fmr1-KO pyramidal neurons were significantly slower and failed to recover from short-term depression as quickly as wild type (WT) synapses. By 4-5 weeks of mPFC development, connectivity rates were identical for both KO and WT pyramidal neurons and synapse dynamics changed from depressing to facilitating responses with similar properties in both groups. We propose that the early alteration in connectivity and synaptic recovery are tightly linked: using a network model, we show that slower synapses are essential to counterbalance hyperconnectivity in order to maintain a dynamic range of excitatory activity. However, the slow synaptic time constants induce decreased responsiveness to low-frequency stimulation, which may explain deficits in integration and early information processing in attentional neuronal networks in NDDs.

Critical period for acoustic preference in mice

“…For example, input-specific synaptic plasticity in frontal cortex is impaired in neurodevelopmental disorders (62), and axonal organization and development in the prefrontal cortex are disrupted in autism (63). Hyperconnectivity and slow synaptic dynamics are observed in the mPFC of the Fmr1 −/− mouse, a model of fragile-X syndrome, autism, and mental retardation (64). Notably, this delay in synaptic maturation arises during the second to third postnatal week of development, largely coinciding with the critical period observed here for developing acoustic preference.…”

Altered Neuronal and Circuit Excitability in Fragile X Syndrome

“…Using multiple patch-clamp recordings of neighboring L5 cortical pyramidal neurons in acute slices of prefrontal cortex from Fmr1 KO mice, a recent study demonstrated that such clusters of neurons are hyperconnected (Fig. 4D) (Testa-Silva et al, 2012). Importantly, this defect was transient and occurred only during a critical period in mouse brain development (2 nd and 3 rd postnatal weeks), which may be particularly important for FXS pathogenesis, since it coincides with a time when Fmr1 KO mice exhibit a variety of other transient synaptic or brain circuit alterations (Bureau et al, 2008; Cruz-Martin et al, 2010; Goncalves et al, 2013; Harlow et al, 2010; He et al, 2014; Meredith et al, 2011).…”

The Default Mode Network in Autism

“…A prominent neurobiological theory postulates that ASD is characterized by an E/I imbalance in local neural circuits that subserve sensory, social, and affective processes (105–109). E/I imbalance in ASD is thought to alter local and global brain signaling and contribute to atypical fluctuations in regional fMRI signals (64, 110), leading to difficulties with modulating flexible and goal-directed behaviors.…”