Severely Attenuated Visual Feedback Processing in Children on the Autism Spectrum.

Individuals on the autism spectrum often exhibit atypicality in their sensory perception, but the neural underpinnings of these perceptual differences remain incompletely understood. One proposed mechanism is an imbalance in higher-order feedback re-entrant inputs to early sensory cortices during sensory perception, leading to increased propensity to focus on local object features over global context. We explored this theory by measuring visual evoked potentials during contour integration as considerable work has revealed that these processes are largely driven by feedback inputs from higher-order ventral visual stream regions. We tested the hypothesis that autistic individuals would have attenuated evoked responses to illusory contours compared with neurotypical controls. Electrophysiology was acquired while 29 autistic and 31 neurotypical children (7-17 years old, inclusive of both males and females) passively viewed a random series of Kanizsa figure stimuli, each consisting of four inducers that were aligned either at random rotational angles or such that contour integration would form an illusory square. Autistic children demonstrated attenuated automatic contour integration over lateral occipital regions relative to neurotypical controls. The data are discussed in terms of the role of predictive feedback processes on perception of global stimulus features and the notion that weakened "priors" may play a role in the visual processing anomalies seen in autism.SIGNIFICANCE STATEMENT Children on the autism spectrum differ from typically developing children in many aspects of their processing of sensory stimuli. One proposed mechanism for these differences is an imbalance in higher-order feedback to primary sensory regions, leading to an increased focus on local object features rather than global context. However, systematic investigation of these feedback mechanisms remains limited. Using EEG and a visual illusion paradigm that is highly dependent on intact feedback processing, we demonstrated significant disruptions to visual feedback processing in children with autism. This provides much needed experimental evidence that advances our understanding of the contribution of feedback processing to visual perception in autism spectrum disorder.

Metacognitive Beliefs and Metacognitive Capacity: Do They Assess Related Phenomena?

ABSTRACT: Metacognition has been defined several ways across different fields. In schizophrenia, two primary approaches to assessing metacognition focus on measuring metacognitive beliefs and metacognitive capacity. The degree of association between these two approaches is unclear. In this pilot study, schizophrenia (n = 39) and control (n = 46) groups were assessed using metacognitive beliefs (Metacognition Questionnaire-30) and metacognitive capacity (Metacognition Assessment Scale-Abbreviated) scales. We also examined how these two approaches predicted quality of life. Results showed anticipated differences for metacognitive beliefs, metacognitive capacity, and quality of life when comparing schizophrenia and healthy control groups. However, metacognitive beliefs and metacognitive capacity were not significantly related and only predicted quality of life in the healthy control group. Although preliminary, these findings suggest that these two approaches have a limited relationship with one another. Future studies should test these findings in larger samples and focus on examining associations at different levels of metacognitive functioning in those with schizophrenia.

The strength of feedback processing is associated with resistance to visual backward masking during Illusory Contour processing in adult humans.

Re-entrant feedback processing is a key mechanism of visual object-recognition, especially under compromised viewing conditions where only sparse information is available and object features must be interpolated. Illusory Contour stimuli are commonly used in conjunction with Visual Evoked Potentials (VEP) to study these filling-in processes, with characteristic modulation of the VEP in the ∼100-150 ms timeframe associated with this re-entrant processing. Substantial inter-individual variability in timing and amplitude of feedback-related VEP modulation is observed, raising the question whether this variability might underlie inter-individual differences in the ability to form strong perceptual gestalts. Backward masking paradig ms have been used to study inter-individual variance in the ability to form robust object perceptions before processing of the mask interferes with object-recognition. Some individuals recognize objects when the time between target object and mask is extremely short, whereas others struggle to do so even at longer target-to-mask intervals. We asked whether timing and amplitude of feedback-related VEP modulations were associated with individual differences in resistance to backward masking. Participants (N=40) showed substantial performance variability in detecting Illusory Contours at intermediate target-to-mask intervals (67 ms and 117 ms), allowing us to use kmeans clustering to divide the population into four performance groups (poor, low-average, high-average, superior). There was a clear relationship between the amplitude (but not the timing) of feedback-related VEP modulation and Illusory Contour detection during backward masking. We conclude that individual differences in the strength of feedback processing in neurotypical humans lead to differences in the ability to quickly establish perceptual awareness of incomplete visual objects.

Stuck Inside: How Social Functioning in Schizophrenia Changed During the COVID-19 Pandemic.

ABSTRACT: Social distancing policies enacted during the COVID-19 pandemic altered our social interactions. People with schizophrenia, who already exhibit social deficits, may have been disproportionally impacted. In this pilot study, we a) compared prepandemic social functioning to functioning during the pandemic in people with schizophrenia ( n = 21) who had data at both time points; and b) examined if patterns of decline in schizophrenia differed from healthy controls ( n = 21) across a series of repeated-measures analyses of variance. We observed larger declines in social functioning in schizophrenia (η 2 = 0.07, medium effect size) during the pandemic compared with the control group. Between-group declines did not extend to other domains, suggesting that declines are specific to social functioning. Our findings signal that treatments focusing on reconnecting people with schizophrenia to their social networks should be prioritized. Future studies should continue tracking social functioning after the pandemic to illustrate patterns of recovery.

Revisiting the Role of Ser982 Phosphorylation in Stoichiometry Shift of the Electrogenic Na+/qHCO3- Cotransporter NBCe1.

In most cell types and heterologous expression systems, the electrogenic sodium-bicarbonate cotransporter NBCe1 operates with a 1Na+-2HCO3- stoichiometry that, given typical transmembrane electrochemical gradients, promotes Na+ and HCO3- influx. However, NBCe1 in the kidney mediates HCO3- efflux (HCO3- reabsorption), a direction that has been predicted to be favored only if NBCe1 operates with a 1:3 stoichiometry. The phosphorylation state of Ser982 in the cytosolic carboxy-terminal domain of NBCe1 has been reported to be a key determinant of the transporter stoichiometry, with non-phosphorylated Ser982 favoring a 1:3 stoichiometry. Conversely, phosphoproteomic data from renal cortical preparations have revealed the presence of NBCe1 peptides including phosphoserine982 (pSer982) and/or pSer985 although it was not known what proportion of NBCe1 molecules were phosphorylated. In the present study, we report the generation, characterization, and application of a novel phosphospecific antibody raised against NBCe1/pSer982 and show that, contrary to expectations, Ser982 is more prevalently phosphorylated in murine kidneys (in which NBCe1 mediates HCO3- efflux) than in murine colons (in which NBCe1 mediates HCO3- influx). Using phosphomimetic mutants of murine NBCe1 expressed in Xenopus oocytes, we found no evidence that the phosphorylation state of Ser982 or Ser985 alone influences the transport stoichiometry or conductance. Furthermore, we found that the phosphorylation of NBCe1/Ser982 is enhanced in murine kidneys following a 24 h induction of metabolic acidosis. We conclude that the phosphorylation status of Ser982 is not a key determinant of NBCe1 stoichiometry but correlates with presumed NBCe1 activity.

Mouse Slc4a11 expressed in Xenopus oocytes is an ideally selective H+/OH- conductance pathway that is stimulated by rises in intracellular and extracellular pH.

The SLC4A11 gene encodes the bicarbonate-transporter-related protein BTR1, which is mutated in syndromes characterized by vision and hearing loss. Signs of these diseases [congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome] are evident in mouse models of Slc4a11 disruption. However, the intrinsic activity of Slc4a11 remains controversial, complicating assignment of its (patho)physiological role. Most studies concur that Slc4a11 transports H+ (or the thermodynamically equivalent species OH-) rather than HCO3-, but disparities have arisen as to whether the transport is coupled to another species such as Na+ or NH3/NH4+ Here for the first time, we examine the action of mouse Slc4a11 in Xenopus oocytes. We simultaneously monitor changes in intracellular pH, membrane potential, and conductance as we alter extracellular pH, revealing the electrical and chemical driving forces that underlie the observed ion fluxes. We find that mSlc4a11 is an ideally selective H+/OH- conductive pathway, the action of which is uncoupled from the cotransport of any other ion. We also find that the activity of mSlc4a11 is independently enhanced by both extracellular and intracellular alkalinization, suggesting OH- as the most likely substrate and providing a novel explanation for the apparent NH3-dependence of Slc4a11-mediated currents reported by others. We suggest that the unique properties of Slc4a11 action underlie its value as a pH regulator in corneal endothelial cells.

A novel mutant Na+ /HCO3- cotransporter NBCe1 in a case of compound-heterozygous inheritance of proximal renal tubular acidosis.

KEY POINTS: The inheritance of two defective alleles of SLC4A4, the gene that encodes the widely-expressed electrogenic sodium bicarbonate cotransporter NBCe1, results in the bicarbonate-wasting disease proximal renal tubular acidosis (pRTA). In the present study, we report the first case of compound-heterozygous inheritance of pRTA (p.Arg510His/p.Gln913Arg) in an individual with low blood pH, blindness and neurological signs that resemble transient ischaemic attacks. We employ fluorescence microscopy on non-polarized (human embryonic kidney) and polarized (Madin-Darby canine kidney) renal cell lines and electrophysiology on Xenopus oocytes to characterize the mutant transporters (R510H and Q913R). Both mutant transporters exhibit enhanced intracellular retention in renal cells, an observation that probably explains the HCO3- transport deficit in the individual. Both mutants retain a close-to-normal per molecule Na+ /HCO3- cotransport activity in Xenopus oocytes, suggesting that they are suitable candidates for folding-correction therapy. However, Q913R expression is uniquely associated with a depolarizing, HCO3- independent, Cl- -conductance in oocytes that could have pathological consequences if expressed in the cells of patients. ABSTRACT: Proximal renal tubular acidosis (pRTA) is a rare, recessively-inherited disease characterized by abnormally acidic blood, blindness, as well as below average height and weight. pRTA is typically associated with homozygous mutation of the solute carrier 4 family gene SLC4A4. SLC4A4 encodes the electrogenic sodium bicarbonate cotransporter NBCe1, a membrane protein that acts to maintain intracellular and plasma pH. We present the first description of a case of compound-heterozygous inheritance of pRTA. The individual has inherited two mutations in NBCe1: p.Arg510His (R510H) and p.Gln913Arg (Q913R), one from each parent. In addition to the usual features of pRTA, the patient exhibits unusual signs, such as muscle spasms and fever. We have recreated these mutant transporters for expression in model systems. We find that both of the mutant proteins exhibit substantial intracellular retention when expressed in mammalian renal cell lines. When expressed in Xenopus oocytes, we find that the R510H and Q913R-mutant NBCe1 molecules exhibit apparently normal Na+ /HCO3- cotransport activity but that Q913R is associated with an unusual HCO3- independent anion-leak. We conclude that a reduced accumulation of NBCe1 protein in the basolateral membrane of proximal-tubule epithelia is the most probable cause of pRTA in this case. We further note that the Q913R-associated anion-leak could itself be pathogenic if expressed in the plasma membrane of mammalian cells, compromising the benefit of strategies aiming to enhance mutant NBCe1 accumulation in the plasma membrane.

Na+-H+ exchanger-1 (NHE1) regulation in kidney proximal tubule.

The ubiquitously expressed plasma membrane Na(+)-H(+) exchanger NHE1 is a 12 transmembrane-spanning protein that directs important cell functions such as homeostatic intracellular volume and pH control. The 315 amino acid cytosolic tail of NHE1 binds plasma membrane phospholipids and multiple proteins that regulate additional, ion-translocation independent functions. This review focuses on NHE1 structure/function relationships, as well as the role of NHE1 in kidney proximal tubule functions, including pH regulation, vectorial Na(+) transport, cell volume control and cell survival. The implications of these functions are particularly critical in the setting of progressive, albuminuric kidney diseases, where the accumulation of reabsorbed fatty acids leads to disruption of NHE1-membrane phospholipid interactions and tubular atrophy, which is a poor prognostic factor for progression to end stage renal disease. This review amplifies the vital role of the proximal tubule NHE1 Na(+)-H(+) exchanger as a kidney cell survival factor.

Meta-analysis of the relationship between metacognition and disorganized symptoms in psychosis.

OBJECTIVE: Disorganized symptoms show associations with metacognitive deficits in psychosis. However, the magnitude of this relationship is unclear. This meta-analysis aimed to 1) quantify relationships between metacognition and both disorganized symptoms and disorganized speech; and 2) examine moderators of these relationships (e.g., metacognition type, neurocognition). METHOD: A literature search was conducted using PsycINFO, Web of Science, PubMed, and EMBASE databases. English-language studies measuring disorganized symptoms and metacognition (i.e., introspective accuracy, metacognitive beliefs, or metacognitive capacity) in psychosis were included. Random effects meta-analyses were conducted using Pearson's r. RESULTS: Meta-analysis of 20 studies (n = 1490) resulted in a significant negative medium correlation between disorganized symptoms and metacognition (r = -0.332, 95 % CI [-0.423, -0.235]). Magnitude was moderated by metacognition type. A significant negative small correlation between disorganized speech and metacognition (r = -0.173, 95 % CI [-0.254, -0.089], n = 1470) was observed, with no significant moderators. CONCLUSIONS: Results clarify the magnitude of the relationships between metacognition and both disorganized symptoms and disorganized speech. Significant relationships may indicate conceptual links, yet the different magnitudes may reflect a distinction between disorganized symptoms and speech. The moderator finding highlights that metacognitive capacity has an especially strong link to disorganized symptoms and underscores the need for careful distinction between types of metacognition in future work.

Narrative Forewarnings: A Qualitative Analysis of the Themes Preceding Disorganized Speech in Schizophrenia.

Disorganized speech is a critical barrier to recovery in schizophrenia, with profound negative impacts on one's ability to engage with the world. Despite the limited efficacy of existing treatments in addressing disorganization, a qualitative analysis of what leads to disorganization in patient narratives has been lacking. This study addresses this gap through inductive thematic analysis of 30 narrative interviews with individuals with schizophrenia, matched based on whether Formal Thought Disorder (FTD) is present. Through this analysis, we identified four core themes (alienation, interpersonal tension, personal benchmarks, and adverse experiences) and eight subthemes. Our findings suggest that disorganization may serve as a protective mechanism against psychological distress and highlight how the severity of FTD influences these themes. Alienation, particularly due to illness-related stigma, emerged more prominently in those with FTD. The themes of personal benchmarks and interpersonal tension pointed towards a heightened sensitivity to social interactions and self-perception among those with schizophrenia. Adverse experiences, encompassing past challenges, suggest a potential link between trauma and symptom exacerbation. Our qualitative analysis of what themes precede disorganized speech has implications for tailoring psychotherapy. By considering an individual's specific triggers and level of disorganization, therapy may be more effectively targeted to improve recovery-based outcomes. By identifying themes within patient narratives, this study advances our understanding of the qualitative aspects preceding disorganized speech in schizophrenia, paving the way for more personalized and effective recovery-focused interventions.

Differential Risk: Gender and Racial Differences in the Relationship between Trauma, Discrimination, and Schizotypy.

Traumatic experiences are associated with increased experiences of positive schizotypy. This may be especially important for People of Color, who experience higher rates of trauma and racial discrimination. No study to date has examined how racial disparities in traumatic experiences may impact schizotypy. Furthermore, of the studies that have examined the relationship between trauma and schizotypy, none have examined racial discrimination as a potential moderator. The present study examined if racial discrimination moderates the relationship between trauma and multidimensional (positive, negative, and disorganized) schizotypy. In a sample of 770 college students, we conducted chi-squared analyses, analyses of variance, and stepwise regressions. We found that Black students experienced significantly higher racial discrimination and trauma than Latinx and Asian students. Furthermore, Black and Latinx students experienced significantly more multidimensional schizotypy items than Asian students. Trauma and racial discrimination explained 8 to 23% of the variance in each dimension of schizotypy. Racial discrimination did not moderate the relationships between trauma and multidimensional schizotypy. Our findings suggest that we need to examine risk factors that may prevent recovery from psychotic disorders. Additionally, disorganized schizotypy showed the most robust associations and may be a critical site of intervention.

Automated measures of speech content and speech organization in schizophrenia: Test-retest reliability and generalizability across demographic variables.

Technological advances in artificial intelligence and natural language processing have increased efficiency of assessing speech content and speech organization in schizophrenia. Despite these developments, there has been little focus on the psychometrics of these approaches. Using two common assessments, the current study addressed this gap by: 1) measuring test-retest reliability; and 2) assessing whether speech content and/or speech organization generalize across demographics. To test these aims, we examined psychometric properties of the Linguistic Inquiry Word Count (LIWC), a speech content measure, and the Coh-Metrix, a speech organization measure. Across baseline to six month (n = 101) and baseline to one year (n = 47) narrative speech samples, we generally observed fair reliability for speech content measures and fair to good reliability for speech organization measures. Regarding demographics, multiple speech indices varied by race, income, and education. The lack of excellent reliability scores for speech indices holds important implications for examining speech variables in clinical trials and highlights the dynamic nature of speech. This work illustrates the importance of designing speech content and speech organization measures with external validity across demographic factors. Future studies examining speech in schizophrenia should account for potential biases against demographic groups introduced by linguistic analysis tools.

Mild vs. moderate: How behavioral speech measures predict metacognitive capacity across different levels of formal thought disorder.

Disorganized speech is a key component of formal thought disorder (FTD) in schizophrenia. Recent work has tied disorganized speech to deficits in metacognition, or one's ability to integrate experiences to form complex mental representations. The level of FTD at which differences in metacognitive capacity emerge remains unclear. Across two studies, using different cut scores to form FTD groups, we aimed to 1) explore the relationship between disorganized speech and metacognition and 2) compare trained rater and automated analysis methods. Clinical interviews were coded for disorganized speech and metacognition using the Communication Disturbances Index (CDI), Coh-Metrix multidimensional indices, and Metacognition Assessment Scale. In Study 1, we examined CDI and Coh-Metrix's ability to predict metacognition in FTD (n = 16) and non-FTD (n = 29) groups. We hypothesized the FTD group would have lower metacognition and that both CDI and Coh-Metrix would account for significant variance in metacognition. In Study 2, we conducted the same analyses with an independent sample using more stringent FTD cut scores (FTD: n = 23; non-FTD: n = 23). Analyses indicated that at a moderate but not mild cutoff: 1) automated methods differentiated FTD and non-FTD groups, 2) differences in metacognition emerged, and 3) behavioral measures accounted for significant variance (34%) in metacognition. Results emphasize the importance of setting the FTD cutoff at a moderate level and using samples that contain high levels of FTD. Findings extend research linking FTD and metacognition and demonstrate the benefit of pairing trained rater and automated speech measures.

Do People With Schizophrenia Enjoy Social Activities as Much as Everyone Else? A Meta-analysis of Consummatory Social Pleasure.

BACKGROUND: The "emotion paradox" of schizophrenia suggests people with schizophrenia demonstrate deficits when reporting anticipated and retrospective pleasure; yet, in-the-moment, consummatory pleasure is largely intact. It is uncertain how these findings extend to social situations. This meta-analysis aimed to (1) determine the mean difference in consummatory social pleasure between people with schizophrenia and healthy controls, and (2) examine moderators of this effect, including study design and clinical characteristics of participants. DESIGN: A literature search using PsycINFO, Web of Science, Pubmed, and EMBASE databases was conducted. Studies measuring consummatory social pleasure using experience sampling methods and laboratory social simulations were included. Random effects meta-analyses were conducted using Hedge's g. RESULTS: Meta-analysis of 26 studies suggests people with schizophrenia exhibited a small, significant deficit in consummatory social pleasure (g = -0.38, 90% CI [-0.53, -0.22]). There was significant heterogeneity in effect sizes; magnitude was moderated by study design and type of measure used to assess social pleasure. CONCLUSIONS: Overall, people with schizophrenia seem to exhibit less consummatory social pleasure than controls. However, this deficit is smaller than in studies of anticipated and retrospective pleasure. Thus, consummatory social pleasure may not be quite as impaired in people with schizophrenia as traditional anhedonia research suggests. Moreover, pleasure deficits observed in people with schizophrenia may result from differences in the quality of their daily social experiences rather than differences in their capacity for social pleasure. Results have important implications for clinical interventions that address barriers to social engagement, low-pleasure beliefs, and cognitive remediation to treat schizophrenia.

Emergence of Language Related to Self-experience and Agency in Autobiographical Narratives of Individuals With Schizophrenia.

BACKGROUND AND HYPOTHESIS: Disturbances in self-experience are a central feature of schizophrenia and its study can enhance phenomenological understanding and inform mechanisms underlying clinical symptoms. Self-experience involves the sense of self-presence, of being the subject of one's own experiences and agent of one's own actions, and of being distinct from others. Self-experience is traditionally assessed by manual rating of interviews; however, natural language processing (NLP) offers automated approach that can augment manual ratings by rapid and reliable analysis of text. STUDY DESIGN: We elicited autobiographical narratives from 167 patients with schizophrenia or schizoaffective disorder (SZ) and 90 healthy controls (HC), amounting to 490 000 words and 26 000 sentences. We used NLP techniques to examine transcripts for language related to self-experience, machine learning to validate group differences in language, and canonical correlation analysis to examine the relationship between language and symptoms. STUDY RESULTS: Topics related to self-experience and agency emerged as significantly more expressed in SZ than HC (P < 10-13) and were decoupled from similarly emerging features such as emotional tone, semantic coherence, and concepts related to burden. Further validation on hold-out data showed that a classifier trained on these features achieved patient-control discrimination with AUC = 0.80 (P < 10-5). Canonical correlation analysis revealed significant relationships between self-experience and agency language features and clinical symptoms. CONCLUSIONS: Notably, the self-experience and agency topics emerged without any explicit probing by the interviewer and can be algorithmically detected even though they involve higher-order metacognitive processes. These findings illustrate the utility of NLP methods to examine phenomenological aspects of schizophrenia.

Semantic and phonetic similarity of verbal fluency responses in early-stage psychosis.

Linguistic abnormalities can emerge early in the course of psychotic illness. Computational tools that quantify similarity of responses in standardized language-based tasks such as the verbal fluency test could efficiently characterize the nature and functional correlates of these disturbances. Participants with early-stage psychosis (n=20) and demographically matched controls without a psychiatric diagnosis (n=20) performed category and letter verbal fluency. Semantic similarity was measured via predicted context co-occurrence in a large text corpus using Word2Vec. Phonetic similarity was measured via edit distance using the VFClust tool. Responses were designated as clusters (related items) or switches (transitions to less related items) using similarity-based thresholds. Results revealed that participants with early-stage psychosis compared to controls had lower fluency scores, lower cluster-related semantic similarity, and fewer switches; mean cluster size and phonetic similarity did not differ by group. Lower fluency semantic similarity was correlated with greater speech disorganization (Communication Disturbances Index), although more strongly in controls, and correlated with poorer social functioning (Global Functioning: Social), primarily in the psychosis group. Findings suggest that search for semantically related words may be impaired soon after psychosis onset. Future work is warranted to investigate the impact of language disturbances on social functioning over the course of psychotic illness.

The role of disease-linked residue glutamine-913 in support of the structure and function of the human electrogenic sodium/bicarbonate cotransporter NBCe1-A.

Mutations in the sodium bicarbonate cotransporter NBCe1 (SLC4A4) cause proximal renal tubular acidosis (pRTA). We recently described a novel pRTA mutation p.Gln913Arg (Q913R), inherited in compound heterozygous form with p.Arg510His (R510H). Q913R causes intracellular retention of NBCe1 and a 'gain of function' Cl- leak. To learn more about the importance of glutamine at position 913, we substituted a variety of alternative amino-acid residues (Cys, Glu, Lys, Leu, Ser) at position 913. Studying cRNA-injected Xenopus oocytes by voltage clamp, we find that most de novo mutants exhibit close-to-normal NBCe1 activity; only Q913K expresses a Cl- leak. Studying transiently-transfected, polarised kidney cells by fluorescence microscopy we find that most de novo mutants (except Q913E) are intracellularly retained. A 3D homology model predicts that Gln913 is located in the gating domain of NBCe1 and neighbours the 3D space occupied by another pRTA-associated residue (Arg881), highlighting an important and conformationally-sensitive region of NBCe1. We conclude that the intracellular retention of Q913R is caused by the loss of Gln at position 913, but that the manifestation of the Cl- leak is related to the introduction of Arg at position 913. Our findings will inform future studies to elucidate the nature and the consequences of the leak.

Effects of Nt-truncation and coexpression of isolated Nt domains on the membrane trafficking of electroneutral Na+/HCO3- cotransporters.

The SLC4 genes are all capable of producing multiple variants by alternative splicing or using alternative promoters. The physiological consequences of such diversity are of great interest to investigators. Here, we identified two novel variants of the electroneutral Na(+)/HCO3- cotransporter NBCn1, one full-length starting with "MIPL" and the other Nt-truncated starting with "MDEL". Moreover, we identified a new promoter of Slc4a10 encoding NBCn2 and a novel type of Nt-truncated NBCn2 starting with "MHAN". When heterologously expressed, the new NBCn1 variants were well localized to the plasma membrane and exhibited characteristic NBCn1 activity. However, MHAN-NBCn2 was poorly localized on the plasma membrane. By deletion mutations, we identified the Nt regions important for the surface localization of NBCn2. Interestingly, coexpressing the full-length NBCn2 greatly enhances the surface abundance of the Nt-truncated NBCn2. Co-immunoprecipitation and bimolecular fluorescence complementation studies showed that the full-length and Nt-truncated NBCn2 interact with each other to form heterodimers in neuro-2A cells. Finally, we showed that the isolated Nt domain interacts with and enhances the surface abundance of the Nt-truncated NBCn2. The present study expands our knowledge of the NBCn1 and NBCn2 transcriptome, and provides insights into how the Nt domain could affect transporter function by regulating its membrane trafficking.