An Investigation on Molecular Mechanisms Underlying Altered Synaptic and Intrinsic Excitability Properties of Medial Prefrontal Pyramidal Neurons in Animal Model of Depression (I)

Depression is the most prevalent form of mental illness. However, neural mechanisms underlying the etiology and clinical manifestations of depressive disorder remain poorly understood. In the present study, two animal models of depression, the forced swim test (FST) and chronic mild stress (CMS) models, are prepared to investigate the cellular and molecular mechanisms underlying the pathogenesis and symptomatology of depression. Clinical, neurophysiological and neuropharmacological studies indicated that malfunction of the medial prefrontal cortex (mPFC) plays a major role in unipolar depression. The pyramidal projection neurons in deep layers of the mPFC play a fundamental role in mediating physiological functions of medial prefrontal cortex. They integrate incoming excitatory or inhibitory signals from various cortical layers and subcortical areas and project, via excitatory glutamatergic axons, to subcortical areas that are potentially involved in the etiology and symptomatology of unipolar depression, such as the amygdala, ventral tegmental area (VTA), and dorsal raphe nucleus (DRN). The mPFC pyramidal projection neurons play a major role in regulating the activity and function of the amygdala, VTA and DRN. Therefore, an altered activity of mPFC pyramidal projection neurons may have a prominent impact on the functions of amygdala, DRN or VTA. Neuroimaging studies demonstrated an association between major depression and abnormal activity of the medial prefrontal cortical areas, suggesting that altered activity of mPFC pyramidal neurons projecting to subcortical areas is involved in the etiology of depressive disorder. In the present study, it is hypothesized that the abnormal activity of mPFC pyramidal projection neurons in depressed patients, resulting from altered synaptic and intrinsic excitability properties, is involved in the pathogenesis and clinical symptoms of depression. To test this hypothesis, mPFC pyramidal neurons projecting to basolateral amygdala (mPFC→BLA), dorsal raphe nucleus (mPFC→DRN) or ventral tegmental area (mPFC→VTA) are identified in brain slices from control rat or rat model of depression and used for whole-cell patch-clamp recordings. It is very likely that abnormal neuronal activity of mPFC pyramidal projection neurons results from the alteration in synaptic transmission and intrinsic excitability property. To further study molecular mechanisms underlying the altered activity of mPFC→BLA, mPFC→DRN or mPFC→VTA pyramidal projection neurons, we will perform the following investigations with the aid of animal model of depression: (1) A perturbation in either 2 glutamatergic or GABAergic neurotransmission could result in hyperactivity or hypoactivity of mPFC pyramidal projection neurons, which subsequently causes various clinical symptoms of major depression. Possible alteration in glutamatergic and GABAergic transmission is investigated by recording evoked glutamatergic EPSCs and GABAergic IPSCs in mPFC→BLA, mPFC→DRN or mPFC→VTA pyramidal projection neurons from control rat or rat model of depression. (2) It is possible that abnormal mPFC activity observed in depressed patients results from altered membrane excitability of mPFC pyramidal projection neurons. To investigate the involvement of altered intrinsic excitability in abnormal mPFC activity observed in depressed patients, whole-cell patch-clamp recordings are performed to study passive and active membrane properties of mPFC→BLA, mPFC→DRN and mPFC→VTA pyramidal projection neurons from control animal or FST/CMS animal models of depression. (3) An impairment of 5-HT neurotransmission in mPFC pyramidal projection neurons may be involved in pathophysiology of unipolar depression. In the present study, whole-cell recordings and confocal [Ca2+]i imaging are performed to investigate possible alteration of serotonergic signaling in mPFC pyramidal projection neurons from FST or CMS model of depression. (4) Cortcicotropin-releasing factor (CRF) plays a crucial role in coordinating autonomic, endocrine and behavior response to stress. It is hypothesized that hyperactivity of CRFergic neurotransmission in the mPFC is involved in the pathophysiology of depression. This hypothesis will be directly tested by investigating CRF1R-mediated electrophysiological effects on mPFC→BLA, mPFC→DRN or mPFC→VTA pyramidal projection neurons from control rat or rat model of depression. The results obtained from the present investigation should shed light on cellular and molecular mechanisms underlying the pathogenesis and symptomatology of depression and lead to the development of possible therapeutic strategies for depressive disorders.

Project ID:PC9408-2177
External Project ID:NSC94-2745-B182-009-URD