Medial prefrontal cortex (mPFC) plasticity brakes expression and executive behaviour in adult Npy1r conditional knockout mice exposed to different maternal care

Experience is a major stimulant of brain plasticity. Early life stress can shape adult's physiology and behaviour through epigenetic changes in the developing limbic system, which may increase vulnerability to neuropathologies. So far, the underlying molecular mechanisms of this important phenomenon remain largely unknown. In the past, limbic Y1 receptor (Y1R) for Neuropeptide Y (NPY) was identified as a key target of maternal care-induced programming of anxiety and energy homeostasis, and findings from clinical studies and pre-clinical animal models support the role of NPY in neuroplasticity, acting as an effective homeostatic modulator of cortical excitatory and inhibitory synaptic transmission. Growing evidences suggest that organized and specialized structures of extracellular matrix, the Perineuronal Nets (PNNs), play a crucial role in modulating the interplay of synaptic excitation and inhibition at the closure of critical periods of enhanced plasticity, but also in adult cortical processing of different stimuli, in an activity-dependent manner. PNNs are known to envelope preferentially parvalbumin (PV) GABAergic neurons, a group of fast-spiking interneurons that are crucial to drive principal neurons activity and refine cortical representations of complex sensory inputs to elicit appropriate behavioural outcomes. Alterations of PNNs-PV system in the medial prefrontal cortex (mPFC) appear to be involved in neuropsychiatric disorders and cognitive and executive dysfunctions. The involvement of PFC in multiple complex behaviours makes it difficult to recapitulate its functions in animal models, however, by using cross-fostering paradigms, extensive behavioural and molecular analysis and stereotactic drug injections on a validated conditional knockout mouse model, the current study aims at investigating (i) if the altered NPY-Y1R system could affect mPFC-related behaviour and (ii) if deficits in executive and cognitive functions in our mice may be ascribed to a different expression of PNNs in the prelimbic cortex (PL). As expected, the anxiety levels of control mice are inversely correlated with the level of maternal care received. An anxious phenotype was also observed in Npy1rrfb mice, where limbic Npy1r gene is selectively deleted only in forebrain excitatory neurons. A new result of this study is that both Npy1rrfb mutants and mice who received low maternal cares, display significant deficits in a specific behavioural test for executive function and problem solving abilities, related to the correct functionality of the mPFC. Interestingly, maternal care seems to affect the molecular pattern of PNNs in PL cortex in a layer-specific manner, whereas the conditional knockout of Y1R may have changed the mPFC microcircuits differently, affecting the level of GABA-ergic maturation. When we injected chondroitinase ABC (Ch-ABC), an enzyme able to dissolve PNNs, locally into the mPFC, we could observe a significant effect on the performance only in the group of mice having experienced low levels of maternal care. Molecularly, these mice were characterized by a particular pattern of PNNs deposition in the PL cortex, whereas mice with the conditional deletion of Npy1r gene and adopted by high caring mothers showed major differences only in PV neuron density, and their behavioural abilities were not affected by Ch-ABC treatment. Together these data suggest a new mechanism in shaping the long-lasting effects of different early life experiences on the mPFC microcircuitry arrangement and on related executive functions, providing an alternative direction for further investigations to identify novel therapeutic approaches to control the homeostatic state in neuropsychiatric disorders.