A Critical Role for Protein Tyrosine Phosphatase Nonreceptor Type 5 in Determining Individual Susceptibility to Develop Stress-Related Cognitive and Morphological Changes

Abstract

While stressful life events confer increased risk for the development of psychopathology, most individuals experiencing adversity maintain normal psychological functioning, suggesting that individual differences may influence the susceptibility to develop stress-related psychiatric disorders. However, little is known about what determines this difference between individuals at the molecular level. In the present study, we identify that protein tyrosine phosphatase nonreceptor type 5 (PTPN5) (also known as STEP) is a critical determinant of differences in individual susceptibility to develop stress-related cognitive and morphological changes in rats. Our data demonstrate that ablation of PTPN5 expression delays physiological recovery from stress and augments the development of stress-related cognitive and morphological changes, whereas overexpression of a constitutively active variant of PTPN5 enhances the individual's resilience to stress. Our data also reveal that reduced PTPN5 expression prolongs the duration of extracellular signal-regulated kinase activation, leading to an elevation of Ca V 1.2 channel expression and a recovery delay of K V 4.2 channels from inactivation, which in turn heightens neuronal vulnerability to glutamate toxicity. Moreover, intraperitoneal injections of L-type Ca 2ϩ channel blocker nifedipine after stress resulted in a significantly lower rate for developing stress-related cognitive and morphological changes seen in PTPN5 knockdown rats. Together, these results identify a novel role for PTPN5 in mediating the development of stress-related cognitive and morphological changes and suggest that people with PTPN5 deficiency may have a greater susceptibility to capture the deleterious effects of stress.

Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis

“…STEP is a known modulator of synaptic plasticity by dephosphorylating subunits of the NMDA receptor promoting their internalization (Goebel-Goody et al, 2012). In fact, STEP has been reported to regulate LTP in the amygdala, and the down-regulation of STEP is thought to play a role in the etiology of stressinduced anxiety disorders (Paul et al, 2007;Yang et al, 2012). As mentioned previously, STEP is specifically expressed in CRF neurons in the dBNST.…”

“…Interestingly, STEP inhibits ERK activity and thereby regulates the duration of ERK-signaling (Valjent et al, 2005;Yang et al, 2012). STEP is specifically expressed in the CRF neurons of the oval BNST while ERK1/2 is found in both cells co-expressing STEP and those not expressing STEP (Dabrowska et al, 2013b).…”

“…For example, in the oval nucleus striatal-enriched protein tyrosine phosphatase (STEP; also called Ptpn5)-immunoreactivity has almost total colocalization with CRF-immunoreactivity, and all Type III neurons express the mRNA for STEP (Dabrowska et al, 2013b). STEP is known to regulate long term potentiation in the amygdala (Paul et al, 2007;Yang et al, 2012) and its role in synaptic plasticity in CRF neurons in the BNST will be discussed later on in this review. Preliminary evidence from our lab suggests the D1 subtype of the dopamine receptor is also specifically expressed in Type III CRF cells in the BNST.…”

Disruption of striatal-enriched protein tyrosine phosphatase (STEP) function in neuropsychiatric disorders

“…The role of STEP in resisting the effects of stress in the brain is the subject of a recent study in rats by Yang et al, 2012, although these studies still need to be expanded to include human populations. The study by Yang and colleagues used a restraint paradigm to analyze impairments in object location memory (OLM), a cognitive task disrupted by stress.…”

“…For example, increased STEP activity is associated with Alzheimer’s disease, schizophrenia, Parkinson’s disease, and fragile X syndrome (Carty et al, 2012; Goebel-Goody et al, 2012b; Kurup et al, 2012; Zhang et al, 2010). In contrast, decreased STEP activity is associated with Huntington’s disease, stroke, brain ischemia, and stress-related anxiety disorders (Deb et al, 2013; Saavedra et al, 2011; Yang et al, 2012). It therefore appears that both high and low levels of STEP can disrupt synaptic functioning, with several mechanisms maintaining STEP expression at optimal levels.…”