Alexander J. Lu

Introduction. Mental health problems are the leading cause of health-related disability in childhood and adolescents worldwide. Despite their lifelong consequences on health, there is a great lack of resources and understanding to address and treat these patients.¹ The treatment of such neuropsychiatric disorders with currently available antidepressants and antipsychotics is challenging because the molecular, cellular, and circuit level etiology of these diseases is not well understood. Therefore, mechanistic investigation of neural circuits in these disorders is essential to developing new targeted, effective treatments. The interaction between parvalbumin (PV+) interneurons and perineuronal nets (PNNs) represent an exciting area of investigation towards understanding and treating these aforementioned disorders.² PNNs modulate PV+ interneuron physiology, and PV+ interneuron dysfunction has been linked to a spectrum of neuropsychiatric disorders associated with perception, learning, and memory deficits.^3,4 This review aims to examine the cellular and molecular mechanisms by which PNNs modulate PV interneuron plasticity and highlights the consequences of this interaction in models of behavioral learning and memory.  Methods. Recombinant mice (Brevican-/-, PV-Cre, PV-Cre;GluA1F/F), immunohistochemistry, super resolution microscopy, slice electrophysiology, Western blot, co-IP assay, qPCR, and the Morris water maze test were used to investigate the synaptic mechanisms of PNNs modulation of PV interneurons.⁵ Behavioral learning and memory experiments utilized the canonical model of fear conditioning and extinction learning to investigate the role of PNNs in learning and memory in the auditory cortex, secondary visual cortex, and amygdala.^6,7,8 Chondroitin ABC lyase via stereotaxic microinjection was used to digest PNNs at each of these brain centers to assess neural circuit function. Results. Brevican (BCAN), an essential PNN component, is a critical regulator of PV+ interneuron plasticity.⁵ PNNs directly influence intrinsic neuronal properties and synaptic composition in response to experience and memory formation. Specifically, BCAN2 achieves this by complexing with both glutamate receptors (GluA1) and fast acting voltage gated K+ channels (Kv1.1 and Kv3.1b), thus altering PV+ interneuron electrophysiology.⁵ Conditioning and PNN digestion experiments show that PNNs are essential in auditory cortex fear consolidation, for recall of remote fear memory encoded by the secondary visual cortex, and for facilitating erasure of drug seeking behavior encoded by the amygdala.^6,7,8   Conclusions. PNNs influence neural circuits of learning and memory by directly altering the electrical properties of PV interneurons. Additionally, PNN degradation provides a window of plasticity facilitating extinction training and behavioral therapy. While further mechanistic investigation is needed, together, these findings present PNNs as potential target for treating neuropsychiatric disorders.

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